BRPI0314344B1 - 2,3-dihydro-6-nitroimidazo [2,1-b] oxazole compound, a pharmaceutical composition comprising the same and method for producing a compound - Google Patents

Abstract

"compound, pharmaceutical composition, and method for producing a compound". 2,3-dihydro-6-nitroimidazo [2,1-b] oxazoles represented by the following general formula (1) [wherein R 13 is hydrogen or C 1-6 alkyl, n is an integer of 0 to 6, r ^ 2 ^ is -or ^ 3 ^ or analog (where r ^ 3 ^ is hydrogen, C 1-6 alkyl, or analog), or r ^ 1 ^ and - (ch ~ 2 ~ ) may be linked via a nitrogen atom to form, together with the adjacent carbon atom, a spiro ring represented by the general formula (h) (wherein r41 is hydrogen, C1-6 alkyl). -6 ~, or analog)]. The compounds exhibit excellent bactericidal activity against tuberculosis bacillus, multiple drug resistant tuberculosis bacilli, and atypical acid-resistant bacteria.

Description

“COMPOUND 2,3-DIIDRO-6-NITROIMIDAZO [2,1-B] OXAZOLE, PHARMACEUTICAL COMPOSITION UNDERSTANDING THE SAME AND METHOD TO PRODUCE A COMPOUND”

TECHNICAL FIELD [0001] The present invention relates to a 2,3-dihydroimidazo [2,1b] oxazole compound.

FUNDAMENTALS OF THE TECHNIQUE [0002] Among the acid-resistant bacteria, the human Mycobacterium tuberculosis has been widely known. One third of the human population is said to be infected with this bacterium. In addition to the human Mycobacterium tuberculosis, Mycobacterium africanum and Mycobacterium bovis are also known to belong to the Mycobacterium tuberoculosis group. These bacteria are known as mycobacteria that are highly pathogenic to humans.

[0003] Against these tuberculosis, treatment is carried out using three agents, rifampicin, isoniazid, and ethambutol (or streptomycin) which are considered as first-line agents, or using four agents, such as the three agents above and pyrazinamide .

[0004] However, as the treatment of tuberculosis requires extremely long-term administration of agents, this can result in low adherence, and treatment often ends in failure.

[0005] In addition, with respect to the agents indicated above, it has been reported that: rifampicin causes liver disease, cold syndrome, drug allergy, and its concomitant administration with other drugs is contraindicated due to the induction of enzyme associated with P450; said isoniazid causes disturbance of the peripheral nervous system and induces severe liver disease when used in combination with rifampicin; said ethambutol causes ocular vision failure due to optic nerve disorder; said streptomycin causes a decrease in hearing ability due to the 8th cranial nerve disorder; and said pyrazinamide causes adverse reactions such as liver disease, gout attack associated with increased uric acid level, vomiting (A Clinician's Guide To Tuberculosis, Michael D. Iseman 2000 by Lippincott Williams

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2/854 & Wilkins, printed in the USA, ISBN 0-7817-1749-3, Tuberculosis, 2nd edition, Fumiyuki Kuze and Takahide Izumi, Igaku-Shoin Ltd., 1992).

[0006] Currently it has been reported that cases in which conventional chemotherapy could not be performed due to adverse reactions to these agents constituted 70% (approximately 23%, 52 cases) of the total number of cases in which the administration of the agents was interrupted ( the total of 228 hospitalized patients who underwent research) (Kekkaku, vol. 74, 77-82, 1999).

[0007] In particular, hepatotoxicity, which is induced by rifampicin, isoniazid, and ethambutol among the 5 agents used in combination for the first-line treatment previously indicated, is known as an adverse reaction that is very often developed. At the same time, Mycobacterium tuberculosis resistant to antituberculous agents, Mycobacterium tuberculosis resistant to multiple drugs and the like have increased, and the presence of these types of Mycobacterium tuberculosis makes treatment more difficult.

[0008] According to research carried out by the World Health Organization (acronyms in English: WHO) (from 1996 to 1999), the proportion of Mycobacterium tuberculosis that is resistant to any of the existing antituberculous agents in relation to the total types of Mycobacterium tuberculosis that has been isolated worldwide reaches 19%, and it has been reported that the proportion of Mycobacterium tuberculosis resistant to multiple drugs is 5.1%. The number of vehicles infected with that drug-resistant Mycobacterium tuberculosis is estimated to be 60,000,000, and there is growing concern that Mycobacterium tuberculosis resistant to multiple drugs will grow in the future (April 2001 as a supplement to the journal Tuberculosis , Scientific Blueprint for TB Drug Development.) [0009] Additionally, the major cause of death for AIDS patients is tuberculosis. It has been reported that the number of humans suffering from tuberculosis and also from HIV reaches 10,700,000 in 1997 (Global Alliance for TB drug development). In addition, mixed tuberculosis and HIV infection are considered to be at least 30 times more likely to develop tuberculosis than

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3/854 under normal circumstances.

[0010] Considering the current situation indicated above, the profile of the desired antituberculous agent is as follows: (1) an agent, which is effective even for Mycobacterium tuberculosis resistant to multiple drugs, (2) an agent that allows short-term chemotherapy , (3) an agent with fewer adverse reactions, (4) an agent that is effective against latent infection Mycobacterium tuberculosis (i.e., latent Mycobacterium tuberculosis), and (5) an orally administrable agent.

[0011] Examples of bacteria known to be pathogenic to humans include bacteria causing MAC infection (Mycobacterium avium-intracellulare complex infection) that are recently expanding, such as Mycobacterium avium and Mycobacterium intracellulare, and atypical acid-resistant bacteria, such as Mycobacterium kansasii , Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortimoum, Mycobacterium fortuitum, Mycobacterium fortuitum, Mycobacterium fortuitum

[0012] Today, there are few effective therapeutic agents for these atypical acid-resistant bacterial infections. In the present circumstances, antituberculous agents such as rifampicin, isoniazid, ethambutol, streptomycin and kanamycin are used in combination, a newquinolone agent that is a therapeutic agent for common bacterial infections, macrolide antibiotics, aminoglycoside antibiotics, and tetracycline antibiotics.

[0013] However, when compared to the treatment of common bacterial infections, the treatment of atypical acid-resistant bacterial infections requires prolonged administration of agents, and there are reported cases in which the infection is altered by one that is intractable, ultimately leading to death. In order to interrupt the present situation indicated above, an agent having a more intense effectiveness is desirable.

[0014] For example, National Publication of International Patent Application No.

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4/854

11-508270 (WO97 / 01562) discloses that a 6-nitro-1,2,3,4-tetrahydro [2,1b] imidazopyran compound has an in vitro bactericidal action against Mycobacterium tuberculosis (H37Rv strain) and Mycobacterium tuberculosis resistant to multiple drugs, and that the above compound has a therapeutic effect on an animal model infected with tuberculosis when it is administered orally and thus is useful as an antituberculous agent.

[0015] However, the compound described in the publication above differs from the compound of the present invention in terms of the basic skeleton, and is considered to be a compound not similar to the inventive compound.

[0016] Kuppsuwamy Nagarajan et al. reported in the European Journal of Medicinal Chemistry, 1989, vol. 24, pp. 631-633 than compounds represented by the following general formula (I):

[0017] where R ¹ represents a hydrogen atom or methyl group and - (ChbjnR ² represents a chloromethyl group, C1-C7 alkyl group, isopropoxymethyl group, 3-propenyloxymethyl group, or unsubstituted phenoxymethyl group, and compounds represented by the same general formula (I) above, where R ¹ and - (ChbjnR ² bind to each other to form a cyclopentane or cyclohexane ring (16 types of compounds in total) have a bactericidal action against Mycobacterium tuberculosis (H37Rv strain) .

[0018] However, the publication above describes that only the 4 types of compounds among the above compounds are effective when administered orally. It also describes that the compound showing the highest activity, that is, the compound (CGI-17341) represented by the general formula (I) above in which R ¹ represents a hydrogen atom and - (ChbjnR ² represents ethyl, presented greater mutagenicity, and that, correspondingly, the development of these series of compounds has been abandoned.

[0019] Additionally, Dilip R. Astekar et al. reported in Antimicrobial Agents and Chemotherapy, February 1993, pp. 183-186 on the antimicrobial profile of

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5/854 compound CGI-17341 above. According to the report, ο compound CGI-17341 has a bactericidal action against Mycobacterium tuberculosis (strain H37Rv) and Mycobacterium tuberculosis resistant to multiple drugs, but it has no activity against atypical acid-resistant bacteria, M. avium, M. intracellulare, and M fortuitum when used at 250 pg / ml or less.

Disclosure of the invention [0020] It is an object of the present invention to provide a compound showing an excellent bactericidal action against Mycobacterium tuberculosis and Mycobacterium tuberculosis resistant to multiple drugs.

[0021] It is another object of the present invention to provide a compound showing an excellent bactericidal action against atypical acid-resistant bacteria.

[0022] As a result of intensive studies, the present inventors have succeeded in synthesizing an unprecedented 2,3-dihydroimidazo [2,1-b] oxazole compound, which has an excellent bactericidal action against Mycobacterium tuberculosis, Mycobacterium tuberculosis resistant to multiple drugs, and atypical acid-resistant bacteria. The present invention was completed based on these findings.

[0023] The present invention provides a 2,3-dihydro-6-nitroimidazo [2,1-b] oxazole compound represented by the following general formula (1), optically active form thereof, or pharmaceutically acceptable salt thereof:

[0024] where R ¹ represents a hydrogen atom or C1-8 alkyl group, n represents an integer from 0 to 6, and R ² represents a group represented by the general formula (A), (B), (C) , (D), (E), (F) or (G) indicated below, and in addition, R ¹ and - (CH2) nR ² can bond together with carbon atoms adjacent to it via atoms nitrogen, to form a spiro ring represented by the general formula (H) indicated below.

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6/854 [0025] General formulas (A) - (H) will be described below:

[0026] a group represented by the following general formula (A):

-OR ³ (A) [0027] where R ³ represents:

A1) hydrogen atom;

A2) C1-8 alkyl group;

A3) C1-6 alkoxy group - C1-6 alkyl

A4) C1-6 phenyl alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a C1-6 phenyl alkoxy group, an unsubstituted or substituted halogen C1-6 alkyl group, a group C1-6 alkoxy unsubstituted or substituted by halogen, and a phenoxy group which may have, as a substituent, at least one C1-6 alkoxy group unsubstituted or substituted by halogen in the phenyl ring);

A5) biphenylyl C1-6 alkyl group;

A6) C2-6 alkenyl phenyl group:

A7) C1-6 alkylsulfonyl group;

A8) benzenesulfonyl group which can be substituted by a C1-6 alkyl group;

A9) C1-8 alkanoyl group;

A10) a group represented by the following general formula (Aa):

[0028] where R ⁴ represents a C1-8 alkoxycarbonyl group; a phenyl C1-6 alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a phenyl C1-6 alkoxy group, a C16 alkyl group unsubstituted or substituted by halogen, and a C1 alkoxy group -6 not replaced or replaced by halogen); or phenyl C1-6 alkyl group (which may be substituted on the phenyl ring by at least one group selected from the group consisting of a phenyl C1-6 alkoxy group, an unsubstituted or substituted halogen C1-6 alkyl group, and

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7/854 a C1-6 alkoxy group unsubstituted or substituted by halogen);

A11) a biphenylyl alkoxycarbonyl group C1-e;

A12) benzoxazolyl C1-6 alkyl group (which can be substituted on the benzoxazole ring by at least one oxo group as a substituent);

A13) benzoxazolyl group; or

A14) oxazolyl C1-6 alkyl group (which can be substituted on the oxazole ring by at least one group selected from the group consisting of a phenyl group and C1-6 alkyl group as a substituent).

[0029] a group represented by the following general formula (B):

-SR ⁵ (B) [0030] where R ⁵ represents a tetrazolyl group (which can be substituted on the tetrazole ring by a C1-6 alkyl group or phenyl group which can have a halogen atom as a substituent), or benzoxazolyl group .

[0031] a group represented by the following general formula (C):

-COOR ⁶ (C) [0032] where R ⁶ represents a C1-6 alkyl group.

[0033] a carbamoyloxy group represented by the following general formula (D):

-OOCNR ⁷ R ⁸ (D) [0034] where R ⁷ and R ⁸ each, in the same or different way, represents any one of:

D1) hydrogen atom;

D2) C1-6 alkyl group;

D3) C1-6 alkyl group substituted by halogen;

D4) C1-6 alkoxycarbonyl group - C1-6 alkyl;

D5) C3-8 cycloalkyl group;

D6) C1-6 phenyl alkyl group (which may be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1 alkoxy group -6 not replaced or replaced by halogen);

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8/854

D7) phenyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted C1-6 alkoxy group or substituted by halogen, a Ci-e alkanoyl group, a carboxyl group, a Ci-e alkoxycarbonyl group, a Ci-e phenyl alkoxycarbonyl group, a carbamoyl group, a Ci-e alkylcarbamoyl group, an aminosulfonyl group, and a morpholino group );

D8) naphthyl group;

D9) pyridyl group; and

D10) R ⁷ and R ⁸ can bond together with nitrogen atoms adjacent to it directly or through other heteroatoms or carbon atoms, in order to form a saturated heterocyclic group shown in any of (D10-1 ) to (D10-3) indicated below, or a heterocyclic group condensed with benzene shown in any one of (D10-4) to (D10-7) indicated below: (D10-1) piperazinyl group represented by the general formula (Da) a follow:

—N \ r ⁹ (Da) [0035] where R ⁹ represents:

(Da1) hydrogen atom;

(Da2) C1-8 alkyl group;

(Da3) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Da4) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not replaced or replaced by

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9/854 halogen);

(Da5) Ci-e alkoxycarbonyl group;

(Da6) C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and a C1 alkoxy group -6 not replaced or replaced by halogen);

(Da7) C3-6 phenyl alkenyloxycarbonyl group (which may have at least one C1-6 alkyl group unsubstituted or substituted by halogen in the phenyl ring); or (Da8) amino group substituted by phenyl C1-6 alkylidene (which can be substituted on the phenyl ring by at least one unsubstituted or substituted C1-6 alkyl group by halogen as a substituent).

(D10-2) a group represented by the following general formula (Db):

--N (Db) [0036] where the dashed line represents that the bond can be a double bond, and R ¹⁰ represents:

(Db1) hydrogen atom;

(Db2) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Db3) phenoxy group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group); or (Db4) phenylamino group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group).

(D10-3) morpholino group;

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10/854 (D10-4) indolinyl group (which can be substituted on the indoline ring by at least one halogen atom as a substituent);

(D10-5) isoindolinyl group (which can be substituted on the isoindoline ring by at least one halogen atom as a substituent);

(D10-6) 1,2,3,4-tetrahydroquinolyl group, (which can be substituted on the ring

1,2,3,4-tetrahydroquinoline with at least one halogen atom as a substituent); and (D10-7) 1,2,3,4-tetrahydroisoquinolyl group, (which can be substituted on the 1,2,3,4-tetrahydroisoquinoline ring by at least one halogen atom as a substituent).

[0037] a phenoxy group represented by the following general formula (E):

[0038] where X represents a halogen atom or C1-6 alkyl group substituted by amino which may have a C1-6 alkyl group as a substituent, m represents an integer from 0 to 3, and R ¹¹ represents:

E1) hydrogen atom;

E2) C1-6 alkyl group unsubstituted or substituted by halogen;

E3) C1-6 alkoxy group unsubstituted or substituted by halogen;

E4) a group represented by the following general formula (Ea): - (W) o-NR ¹² R ¹³ (Ea) [0039] where W represents a -CO- group or a C1-6 alkylene group, o represents a integer 0 or 1, and R ¹² and R ¹³ each, in the same or different way, represents any of:

(Ea1) hydrogen atom;

(Ea2) C1-8 alkyl group;

(Ea3) Ci-e alkanoyl group;

(Ea4) Ci-e alkoxycarbonyl group;

(Ea5) C1-6 phenyl alkyl group (which can be substituted on the phenyl ring by

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11/854 at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent), and the alkyl moiety may be substituted by an alkoxy group C1-e);

(Ea6) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Ea7) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Ea8) pyridyl group (which can be substituted on the pyridine ring by at least one halogen atom as a substituent);

(Ea9) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Ea10) C1-6 alkyl phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not replaced or replaced by

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12/854 one or or halogen); and (Ea11) C1-6 benzoyl alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of halogen atom, an unsubstituted C1-6 alkyl group substituted by halogen, and a C1 alkoxy group -6 unsubstituted replaced by halogen).

E5) imidazolyl group;

E6) triazolyl group;

E7) morpholino group;

E8) thiomorpholino group;

E9) thiomorpholino s-oxide group;

E10) piperidyl group represented by the following general formula (Eaa):

-(Won

R ¹⁴

R ^14A (Eaa) of [0040] where W and o are as indicated above, R ^14A represents a hydrogen atom, hydroxyl group, C1-e alkoxy group, or phenyl group (which can be substituted by halogen in the phenyl ring); the dashed line represents that the bond can be a double bond, and when the dashed line represents a double bond, this means that only R ¹⁴ is substituted; R ¹⁴ and R ^14A can bond together with carbon atoms adjacent to it to form a C 1-4 alkylenedioxy group, and R ¹⁴ represents:

(Eaa1) hydrogen atom;

(Eaa2) Ci-e alkoxycarbonyl group;

(Eaa3) phenoxy group (which can be substituted on the phenyl ring by at least one of the selected group consisting of

Unsubstituted C1-6 of or an atom substituted by alkyl group alkoxy group C1-4 alkylenedioxy group; a C1C1-6 alkoxycarbonyl group unsubstituted or substituted by a halogen group; halogen; halogen;

and; a cyan group; a C2-6 alkenyl group; a nitro group; a phenyl group; an amino group that can have, as a substituent, a

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13/854 group selected from the group consisting of a phenyl group, a C1-6 alkyl group, a carbamoyl group and a C1-8 alkanoyl group; a C1-6 alkyl group substituted by C1-6 alkanoyl; a hydroxyl group; a C1-6 alkyl group substituted by C1-6 alkoxycarbonyl; a phenyl C 1-6 alkyl group; an Ci-e alkanoyl group; a C 1-6 alkylthio group; a 1,2,4 triazolyl group; an isoxazolyl group; an imidazolyl group; a benzothiazolyl group; a 2H-benzotriazolyl group; a pyrrolyl group; a benzoxazolyl group; a piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from the group consisting of a C1-6 alkoxycarbonyl group and a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one selected group) of the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent); a piperidinyl group (which can be substituted on the piperidine ring by at least one group selected from the group consisting of an amino group (which can be substituted on the amino group by at least one group selected from the group consisting of a C1-6 alkyl group) and a phenyl group (which may be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or substituted by halogen) as a substituent), and a carbamoyl group));

(Eaa4) hydroxyl group;

(Eaa5) carboxy group;

(Eaa6) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom , a C1-6 alkyl group unsubstituted or substituted by halogen, and a

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14/854 C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent), a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent);

(Eaa7) C1-6 alkoxy group;

(Eaa8) C3-8 cycloalkyl group - C1-8 alkoxy;

(Eaa9) phenylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Eaa10) tetrahydropyranyloxy group;

(Eaa11) 1,3-dioxolanyl group;

(Eaa12) oxo group;

(Eaa13) naphthyloxy group (which can be substituted on the naphthalene ring by at least one C1-6 alkyl group as a substituent);

(Eaa14) 2,3-dihydrobenzofuryloxy group (which can be substituted on the 2,3-dihydrobenzofuran ring by at least one group selected from the group consisting of a C1-6 alkyl group and an oxo group);

(Eaa15) benzothiazolyloxy group (which can be substituted on the benzothiazole ring by at least one C1-8 alkyl group);

(Eaa16) 1,2,3,4-tetrahydronaphthoxy group (which can be substituted on the ring

1,2,3,4-tetrahydronaphthalene by at least one oxo group as a substituent);

(Eaa17) 1,3-benzoxathiolaniloxy group (which can be substituted on the ring on the 1,3-benzoxathiolane by at least one oxo group as a substituent);

(Eaa18) isoquinolyloxy group;

(Eaa19) pyridyloxy group;

(Eaa20) quinolyloxy group (which can be replaced on the quinoline ring by

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15/854 at least one C1-6 alkyl group as a substituent);

(Eaa21) dibenzofuryloxy group;

(Eaa22) 2H-chromenyloxy group (which can be substituted on the 2Hchromene ring by at least one oxo group as a substituent);

(Eaa23) benzisoxazolyloxy group;

(Eaa24) quinoxalyloxy group;

(Eaa25) 2,3-dihydro-1 H-indenyloxy group (which can be substituted on the ring

2,3-dihydro-1 H-indene by at least one oxo group as a substituent);

(Eaa26) benzofurazaniloxy group; or (Eaa27) C2-6 alkenyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and one C1-6 alkoxy group not substituted or substituted by halogen).

E11) a group represented by the following general formula (Eab):

- (WQo— N — R ¹⁵ (Eab) [0041] where o is the same as above, W1 represents a C1-6 alkylene group and R ¹⁵ represents:

(Eab1) hydrogen atom;

(Eab2) C1-6 alkyl group (the alkyl group being substituted by a morpholino group, benzoyl group, carbamoyl group which can have a C1-6 alkyl group as a substituent, or cyano group);

(Eab3) C3-8 cycloalkyl group;

(Eab4) C1-6 phenyl alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, a phenyl group, a nitro group, a C1- alkylthio group 6, a C1-6 alkylsulfonyl group, a C1-6 phenyl alkoxy group, a C2-6 alkanoyloxy group, an unsubstituted C1-6 alkyl group or

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16/854 substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a 1,2,3-thiadiazolyl group);

(Eab5) C2-6 alkenyl group;

(Eab6) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkyl group unsubstituted or substituted by halogen, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Eab7) Ci-e alkanoyl group;

(Eab8) C2-6 phenyl alkanoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Eab9) benzoyl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Eab10) C1-20 alkoxycarbonyl group (which can be substituted in the alkoxy group by at least one group selected from the group consisting of a halogen atom, an amino group which can have a C1-6 alkyl group as a substituent, and a C1-6 alkoxy group substituted by C1-6 alkoxy);

(Eab11) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, an alkoxy group C1-6 unsubstituted or substituted by halogen, a nitro group, a C 1-6 alkylthio group unsubstituted or substituted by halogen, an amino group that can

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17/854 has a C1-6 alkanoyl group, a C1-6 phenyl alkoxy group, a C1-6 alkoxycarbonyl group, and a 1,2,3-thiadiazolyl group);

(Eab12) a C3-6 phenyl alkenyloxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a group C1-6 alkoxy not substituted or substituted by halogen);

(Eab13) phenoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Eab14) phenyl C1-6 alkylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Eab15) phenylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a non-C1-6 alkoxy group substituted or substituted by halogen);

(Eab16) C1-6 alkoxycarbonyl group substituted by benzofuryl which can be substituted by at least one halogen atom in the benzofuran ring;

(Eab17) C 1-6 benzothienyl alkoxycarbonyl group (which can be substituted on the benzothiophene ring by at least one group selected from the group consisting of a halogen atom and an unsubstituted or substituted C 1-6 alkoxy group as a substituent);

(Eab18) C1-6 alkoxycarbonyl group substituted by naphthyl;

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18/854 (Eab19) C1-6 alkoxycarbonyl group substituted by pyridyl (which can be substituted on the pyridine ring by at least one halogen atom as a substituent);

(Eab20) C1-6 alkoxycarbonyl group substituted by furyl (which can be substituted on the furan ring by at least one nitro group as a substituent);

(Eab21) C1-6 alkoxycarbonyl group substituted by thienyl (which may have at least one halogen atom as a substituent on the thiophene ring);

(Eab22) C1-6 alkoxycarbonyl group substituted by thiazolyl (which can be substituted on the thiazole ring by at least one group selected from the group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted on the phenyl ring by at least one C1-6 alkyl group not substituted or substituted by halogen));

(Eab23) C1-6 alkoxycarbonyl group substituted by tetrazolyl (which can be substituted on the tetrazole ring by at least one group selected from the group consisting of a C1-6 alkyl group and a phenyl group (which can have at least one halogen atom) as a substituent on the phenyl ring) as a substituent);

(Eab24) 2,3-dihydro-1 H-indenyloxycarbonyl group;

(Eab25) C1-6 alkoxycarbonyl group replaced by adamantane;

(Eab26) phenyl C3-6 alkynyloxycarbonyl group;

(Eab27) C 1-6 alkoxycarbonyl phenylthio group;

(Eab28) C1-6 alkoxycarbonyl group substituted by phenyl C1-6 alkoxy;

(Eab29) C2-6 alkenyloxycarbonyl group;

(Eab30) C2-6 alkynyloxycarbonyl group;

(Eab31) C1-6 alkoxycarbonyl group substituted by C3-8 cycloalkyl; or (Eab32) C1-6 alkoxycarbonyl group substituted by benzoyl.

E12) a group represented by the following general formula (Eb):

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19/854

N — R ¹⁶ (Eb) [0042] where the dashed line represents that the bond can be a double bond, and R ¹⁶ is defined as the same as R ¹⁵ ;

E13) a group represented by the general formula (Ec) below:

N — R ¹⁷ (Ec) [0043] —c — N

II 'O in which R ¹⁷ represents:

(Ec1) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Ec2) C1-4 alkoxycarbonyl group; or (Ec3) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and a C1-6 alkoxy group not substituted or substituted by halogen).

E14) pyridyl group;

E15) a group represented by the following general formula (Ee):

-O

N — R ⁴⁶ (Ee) where R ⁴⁶ represents a phenyl group (which can be substituted on the [0044] phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted C1-6 alkyl group or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent); C1-6 alkyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an alkyl group

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20/854

C1-6 unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen); C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a C1-6 alkoxy group not substituted or substituted by halogen); or C1-6 alkoxycarbonyl group.

E16) phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced with halogen);

E17) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced with halogen);

E18) 8-azabicyclo [3,2,1] octyl group (which can be substituted on the 8azabicyclo [3,2,1] octane ring by at least one phenoxy group (which can be substituted on the phenyl ring by at least one selected group the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent);

E19) a group represented by the following general formula (Ef): -CH = N-NR ⁴⁷ R ⁴⁸ (Ef) [0045] where R ⁴⁷ and R ⁴⁸ each, in the same or different way, represents any one of a hydrogen atom, a C1-6 alkyl group, a phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen , and a C1-6 alkoxy group unsubstituted or substituted by halogen), or a pyridyl group (which can be substituted on the pyridine ring by at

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21/854 minus a C1-6 alkyl group unsubstituted or substituted by halogen as a substituent); and in addition, R ⁴⁷ and R ⁴⁸ can bond together with nitrogen atoms adjacent to it directly or through other hetero atoms, to form a 5-7 membered saturated heterocyclic ring, which can be substituted on the ring heterocyclic with at least one phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a C1- alkoxy group 6 not substituted or substituted by halogen) as a substituent;

E20) C1-6 alkoxy phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and a C1 alkoxy group -6 not replaced or replaced by halogen);

E21) C2-6 alkenyl group substituted by amino (which can be substituted in the amino group by at least one group selected from the group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted in the phenyl ring by at least a group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen)); or

E22) oxazolidinyl group (which can be substituted on the oxazolidine ring by at least one oxo group as a substituent).

[0046] a group represented by the following general formula (F):

-NR ¹⁹ R ²⁰ (F) [0047] where R ¹⁹ and R ²⁰ each, in identical or different form, represents any one of:

F1) hydrogen atom;

F2) C1-8 alkyl group;

F3) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at

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22/854 minus a group selected from the group consisting of: a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group halogen, and a C1-6 alkoxy group not substituted or substituted by halogen); a halogen atom; a C1-6 alkyl group unsubstituted or substituted by halogen; a C1-6 alkoxy group unsubstituted or substituted by halogen; an amino group that can have at least one group selected from the group consisting of a C1-6 alkyl group, and a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen); a piperazinyl group (which can be substituted on the piperazine ring by at least one phenyl C 1 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a non-C 1-6 alkyl group) substituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen) as a substituent); and a piperidyl group (which can be substituted on the piperidine ring by at least one amino group that can have a group selected from the group consisting of a phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group that consists of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) and a C1-6 alkyl group as a substituent));

F4) C1-6 alkyl phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group)

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23/854 halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

F5) C1-6 alkyl amino group (which can be substituted in the amino group by at least one group selected from the group consisting of a C1-6 alkyl group, a C1-6 alkoxycarbonyl group, and a phenyl group that can be substituted in the phenyl group by at least one group selected from a group consisting of a halogen atom and a C1-6 alkyl group not substituted or substituted by halogen);

F6) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen), and a C1-6 alkoxycarbonyl group);

F7) C1-6 alkoxycarbonyl group;

F8) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

F9) a group represented by the following general formula (Fa):

—Ch ₂ ch ₂ —N \ r ²¹ (Fa) [0048] where R ²¹ represents an alkoxycarbonyl group Ci-e; a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, an unsubstituted or substituted halogen C1-6 alkyl group, and a C1-6 alkoxy group not substituted or substituted by halogen); C1-6 alkyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of

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24/854 of a halogen atom and an unsubstituted or substituted halogen C1-6 alkyl group); or phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1- alkoxy group 6 not replaced or replaced by halogen);

F10) group 1 -substituted-4-piperidyl represented by the formula (Fb) below):

(Fb) [0049] where R ²² represents a C1-8 alkoxycarbonyl group; a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a C1- alkoxy group 6 not replaced or replaced by halogen); or phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1- alkoxy group 6 not replaced or replaced by halogen);

F11) C1-6 alkyl piperidyl group (which may have at least one phenoxy group (which may have at least one C1-6 alkyl group unsubstituted or substituted by halogen as a substituent) as a substituent);

F12) in addition, R ¹⁹ and R ²⁰ can bond to each other together with nitrogen atoms adjacent to them directly or through other heteroatoms or carbon atoms, in order to form a heterocyclic ring shown in any of (F12- 1) to (F12-10) indicated below:

(F12-1) a group represented by the following formula (Fc):

(Fc)

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25/854 [0050] where the dashed line represents that the bond can be a double bond, and R ²³ represents:

(Fc1) C1-8 alkyl group;

(Fc2) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fc3) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of: a halogen atom; a C1-6 alkyl group unsubstituted or substituted by halogen; a C1-6 alkoxy group not substituted or substituted by halogen, an amino group which may have, as a substituent, a group selected from the group consisting of a C1-6 alkyl group and a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least a group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen); a phenoxy group (which can be substituted in the phenyl ring with at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by h a C1-6 phenyl alkoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a group C1-6 alkoxy not substituted or substituted by halogen); and a piperidyl group (which may have, on the piperidine ring, as a substituent, at least one amino group which may have a group selected from the group consisting of a phenyl C 1-6 alkyl group (which may be substituted on the phenyl ring by

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26/854 at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) and a C1-6 alkyl group -and));

(Fc4) phenyl C1-6 alkoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fc5) biphenyl C1-6 alkoxy group;

(Fc6) phenyl C3-6 alkenyloxy group that can be substituted on the phenyl ring by at least one halogen atom;

(Fc7) phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkyl group unsubstituted or substituted by halogen, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fc8) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Fc9) Ci-e alkoxycarbonyl group;

(Fc10) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one C1-6 alkoxy group unsubstituted or substituted by halogen);

(Fc11) phenyl C 1-6 alkylcarbamoyl group with at least one halogen being substituted on the phenyl ring;

(Fc12) phenylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a

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27/854 halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen);

(Fc13) phenylthio group (which can be substituted on the phenyl ring by at least one C1-6 alkoxy group unsubstituted or substituted by halogen);

(Fc14) phenyl sulfoxide (which can be substituted on the phenyl ring by at least one unsubstituted or substituted halogen C1-6 alkoxy group);

(Fc15) C 1-6 alkoxy pyridyl group; or (Fc16) a group represented by the following general formula (Fca): - (C = O) o-NR ²⁴ R ²⁵ (Fca) [0051] where o is the same as above, and each of R ²⁴ and R ²⁵ stands for:

(Fca1) hydrogen atom;

(Fca2) C1-8 alkyl group;

(Fca3) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fca4) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fca5) Ci-e alkanoyl group;

(Fca6) phenyl alkanoyl group C2-6 which can be substituted on the phenyl ring by at least one halogen atom;

(Fca7) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group)

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28/854 halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Fca8) Ci-e alkoxycarbonyl group;

(Fca9) C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fca10) phenylcarbamoyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group);

(Fca11) piperidyloxycarbonyl group (which can be substituted on the piperidine ring by at least one phenyl group (which can be substituted on the phenyl ring by at least one unsubstituted or substituted halogen C1-6 alkyl group) as a substituent); or (Fca12) R ²⁴ and R ²⁵ can form a 5-6 membered saturated heterocyclic ring by means of nitrogen atoms adjacent to it, which can be substituted on the heterocyclic ring by at least one group selected from the group consisting of a group C 1-6 alkoxycarbonyl; a benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced by halogen); a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced by halogen); a C1-6 alkyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted C1-6 alkyl group or

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29/854 substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen); a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a C1- alkoxy group 6 not replaced or replaced by halogen); a C2-6 phenyl alkenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1- alkoxy group 6 not replaced or replaced by halogen); and a phenyl group (which may be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced with halogen).

(F12-2) 4-substituted-1-piperazinyl group represented by the following general formula (Fd):

- | / N — R ²⁶ (Fd) [0052] where R ²⁶ represents:

(Fd1) hydrogen atom;

(Fd2) C1-8 alkyl group;

(Fd3) C3-8 cycloalkyl group;

(Fd4) C3-8 cycloalkyl group C1-8 alkyl;

(Fd5) C1-6 alkoxycarbonyl group C1-6 alkyl;

(Fd6) phenyl C2-6 alkenyl group;

(Fd7) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from the group consisting of: a halogen atom; a cyano group; an unsubstituted or substituted C1-6 alkyl group halogen; C3-8 cycloalkyl group; a C1-6 alkoxy group

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30/854 not substituted or substituted by halogen; an amino group that may have a C 1-6 alkyl group as a substituent; a C 1-6 alkoxycarbonyl group; a phenoxy group; a C1-6 phenyl alkyl group; a C2-6 phenyl alkenyl group; a pyridyl group; an imidazolyl group; and a piperidyl group);

(Fd8) biphenylyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1 alkoxy group -6 unsubstituted or substituted by halogen, and an amino group that may have a C16 alkyl group as a substituent);

(Fd9) C1-6 alkyl naphthyl group;

(Fd10) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of: a halogen atom; a cyano group; an amino group that may have a C1-6 alkyl group as a substituent; a C1-6 alkyl group unsubstituted or substituted by halogen; a C1-6 alkoxy group unsubstituted or substituted by halogen; a C1-6 alkoxycarbonyl group; a carboxyl group, a phenoxy group (which can be substituted on the phenyl ring by at at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen); a C1-6 alkyl group ( which can have at least one group selected from the group consisting of a phenyl group in the amino group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a g C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) and a C1-6 alkyl group)); and a phenyl C1-6 alkoxy group (which can be substituted on the phenyl ring by at least one

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31/854 group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen));

(Fd11) biphenyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group);

(Fd12) amino group, amino group that is substituted by a C1-6 alkoxycarbonyl group, phenyl C1-6 alkylamino group (which can be substituted on the phenyl ring by at least one unsubstituted or substituted halogen C1-6 alkyl group), or phenylamino group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of an unsubstituted or substituted C1-6 alkyl group with halogen and a halogen atom);

(Fd13) benzoyl C1-6 alkyl group (which may have at least one halogen atom in the phenyl ring as a substituent);

(Fd14) phenylcarbamoyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one unsubstituted or substituted halogen C1-6 alkyl group);

(Fd15) C1-6 alkyl thiazolyl group (which can be substituted on the thiazole ring by at least one group selected from the group consisting of an unsubstituted or halogen substituted phenyl group and a C1-6 alkyl group);

(Fd16) oxazolyl C1-6 alkyl group (which can be substituted on the oxazole ring by at least one group selected from the group consisting of a phenyl group unsubstituted or substituted by halogen and a C1-6 alkyl group);

(Fd17) indolyl C1-8 alkyl group;

(Fd18) C1-6 furyl alkyl group (which can be substituted on the furan ring by at least one unsubstituted or halogen substituted phenyl group);

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32/854 (Fd19) C1-6 imidazolyl alkyl group (which can be substituted on the imidazole ring by a phenyl group);

(Fd20) quinolyl C1-6 alkyl group;

(Fd21) tetrazolyl group (which can be replaced on the tetrazole ring by a phenyl group);

(Fd22) pyrimidyl group that can be replaced by a phenyl group;

(Fd23) pyridyl group;

(Fd24) benzoxazolyl group;

(Fd25) benzothiazolyl group;

(Fd26) benzoxazolyl C1-6 alkyl group (which may have at least one oxo group on the benzoxazole ring as a substituent);

(Fd27) C2-6 alkanoyl phenoxy group that can be substituted on the phenyl ring by a halogen atom;

(Fd28) C 2-6 alkanoyl phenylthio group which can be substituted on the phenyl ring by a halogen atom;

(Fd29) C2-6 phenyl alkanoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fd30) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted C1-6 alkoxy group or substituted by halogen, and an amino group that may have a C16 alkyl group as a substituent);

(Fd31) biphenylylcarbonyl group;

(Fd32) pyridylcarbonyl group;

(Fd33) phenyl C2-6 alkenylcarbonyl group in which a halogen atom can be substituted on the phenyl ring;

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33/854 (Fd34) phenyl C 1-6 alkylsulfonyl group in which a halogen atom can be substituted on the phenyl ring;

(Fd35) benzenesulfonyl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a halogen atom and a C1-8 alkyl group);

(Fd36) a group represented by the following general formula (Fda):

-COOR ²⁷ (Fda) [0053] where R ²⁷ represents:

(Fda1) C1-8 alkyl group unsubstituted or substituted by halogen;

(Fda2) C3-8 cycloalkyl group;

(Fda3) C3-8 cycloalkyl group - C1-8 alkyl;

(Fda4) C1-6 alkoxy group - C1-6 alkyl;

(Fda5) amino C1-6 alkyl group which may have a C1θ alkyl group;

(Fda6) a group represented by the following general formula (Fdb):

[0054] where R ²⁸ , R ²⁹ , and R ³⁰ represent a hydrogen atom, a C1-e alkyl group, or a phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen), respectively;

(Fda7) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5 groups selected from the group consisting of: a halogen atom; a C1-6 alkyl group unsubstituted or substituted by halogen; a group C1-6 alkoxy unsubstituted or substituted by halogen; a C1-6 alkylthio group unsubstituted or substituted by halogen; a phenyl C1-6 alkoxy group; a hydroxy group; a C1-6 alkylsulfinyl group; a C1-6 alkylsulfonyl group; alkylsulfonyloxy group

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34/854

Ci-e; a cyan group; an Ci-e alkanoyl group; a benzoyl group; a C 1-6 phenyl alkyl group which may have a C 1-6 alkoxy group on the alkyl moiety; an amino group; a nitro group; a carbamoyl group; a C1-8 alkanoylamino group; a C 1-6 alkoxycarbonyl group; a C1-6 alkylaminocarbonyl group; a C1-8 alkoxycarbonylamino group; a C1-6 tri-alkylsilyloxy group; a pyrrolyl group; a tetrahydropyranyloxy group; and an imidazolyl group);

(Fda8) biphenylyl C1-6 alkyl group;

(Fda9) benzhydryl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a halogen atom, a trifluoromethyl group, and a trifluoromethoxy group);

(Fda10) C1-6 alkyl phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fda11) C2-6 phenyl alkynyl group (which can be substituted on the phenyl ring by at least one unsubstituted C1-6 alkyl group or substituted by halogen as a substituent);

(Fda12) C1-6 alkyl pyridyl group;

(Fda13) a group represented by the following general formula (Fdc):

(Fdc) [0055] where R ³¹ represents a phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, an unsubstituted C1-6 alkyl group or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen); C1-6 alkyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group

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35/854 unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen); or benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced by halogen).

(Fda14) C1-6 alkyl piperidine group (which can be substituted on the piperidine ring by a phenoxy group which can have at least one alkyl group unsubstituted or substituted by halogen as a substituent on the phenyl ring);

(Fda15) C1-6 alkyl amino group which may have, as a substituent, at least one group selected from the group consisting of a C1-6 alkyl group and a phenyl group which may have, as a substituent, a C1- alkoxy group 6 not substituted or substituted by halogen in the phenyl ring;

(Fda16) 1,2,3,6-tetrahydropyridyl C1-6 alkyl group (which can be substituted on the 1,2,3,6-tetrahydropyridine ring by at least one phenyl group which may have, as a substituent, at least one C1-6 alkoxy group unsubstituted or substituted by halogen in the phenyl ring);

(Fda17) C1-6 alkyl naphthyl group;

(Fda18) fluorophenyl C1-6 alkyl group;

(Fda19) C1-6 alkyl pyridyl group;

(Fda20) furyl C1-6 alkyl group (which can be substituted on the furan ring by an unsubstituted or halogen substituted phenyl group);

(Fda21) thienyl C1-6 alkyl group;

(Fda22) oxazolyl C1-6 alkyl group (which can be replaced on the oxazole ring by a halogen atom or an unsubstituted or substituted halogen phenyl group);

(Fda23) oxadiazolyl C1-6 alkyl group (which can be substituted on the oxadiazole ring by an unsubstituted or halogen substituted phenyl group);

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36/854 (Fda24) C 1-6 pyrazolyl alkyl group (which can be substituted on the pyrazole ring by an unsubstituted or halogen substituted phenyl group);

(Fda25) C 1-6 benzothienyl alkyl group (which can be substituted on the benzothiophene ring by at least one group selected from the group consisting of a halogen atom and an unsubstituted or substituted halogen C 1-6 alkoxy group);

(Fda26) C1-6 thienyl alkyl group that can be substituted on the thiophene ring by a halogen atom;

(Fda27) benzothiazolyl C1-6 alkyl group;

(Fda28) benzofuryl C1-6 alkyl group that can be substituted on the benzofuran ring by a halogen atom;

(Fda29) C1-6 alkyl indolinyl group (which can be substituted on the indoline ring by at least one group selected from the group consisting of a C1-6 alkyl group and an oxo group);

(Fda30) C1-6 benzoxazolyl alkyl group (which can be substituted on the benzoxazole ring by at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group, and an oxo group);

(Fda31) chromenyl C1-6 alkyl group;

(Fda32) 1,2,3,4-tetrahydroquinolyl C1-6 alkyl group (which can be substituted on the quinoline ring by at least one group selected from the group consisting of a C1-6 alkyl group and an oxo group);

(Fda33) C1-6 alkyl thiazolyl group (which can be substituted on the thiazole ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or halogen substituted phenyl group, and a Ci-e alkyl group ); or (Fda34) C1-6 tetrazolyl alkyl group (which can be substituted on the tetrazole ring by a group selected from the group consisting of an unsubstituted or halogen substituted phenyl group and a C1-6 alkyl group);

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37/854 (Fd37) a group represented by the following general formula (Fe): -Z-NR ³² R ³³ (Fe) [0056] where Z represents -C = O or -C = S, and R ³² and R ³³ each, in an identical or different way, represents any of:

(Fe1) hydrogen atom;

(Fe2) C1-8 alkyl group;

(Fe3) C3-8 cycloalkyl group;

(Fe4) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fe5) C2-6 phenyl alkenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fe6) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen); and (Fe7) R ³² and R ³³ can bond together with nitrogen atoms adjacent to it through other carbon atoms, to form a piperidine ring or 1,2,3,6-tetrahydropyridine ring, which can be substituted on the piperidine ring or 1,2,3,6-tetrahydropyridine by a phenyl group, which can be substituted by at least one group selected from the group consisting of a halogen atom and an unsubstituted C1-6 alkyl group or replaced with halogen.

(Fd38) a group represented by the following general formula (Ff):

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38/854

R ³⁴

-N = C \ ₃₅ (Ff) [0057] where R ³⁴ represents a hydrogen atom or C 6 lower alkyl group, and R ³⁵ represents:

(Ff1) C3-8 cycloalkyl group;

(Ff2) C3-8 cycloalkenyl group;

(Ff3) a group represented by the following general formula (Ffa):

[0058] wherein each of R ³⁶ , R ³⁷ , and R ³⁸ represents: a hydrogen atom; C1-e alkyl group; phenyl group (which can be substituted on the phenyl ring by at least 1 to 5 groups selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted C1-6 alkoxy group or substituted by halogen, a C1-4 alkylenedioxy group, a C1-6 alkylsulfonyl group, an unsubstituted or substituted C1-6 alkylthio group, a nitro group, and an amino group that may have a C1-6 alkanoyl group as a substituent); benzofuhla group (which can be substituted on the benzofuran ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group halogen); biphenylyl group; fuhla group (which can be substituted on the furan ring by a phenyl group which can have a halogen atom as a substituent); or thiazolyl group (which can be substituted on the thiazole ring by at least one phenyl group which can have a halogen atom as a substituent).

(Ff4) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of: a halogen atom; a C1-6 alkyl group unsubstituted or substituted by halogen; a C3-8 cycloalkyl group; a hydroxyl group; a C1-8 alkoxy group unsubstituted or substituted by halogen; a group

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39/854 C3-8 cycloalkyloxy; a C 1-4 alkylenedioxy group; a cyan group; a nitro group; a C2-6 phenyl alkenyl group; a C2-6 alkanoyloxy group; an amino group that may have a C1-6 alkanoyl group as a substituent; a C1-6 alkylsulfonylamino group; a C1e phenyl alkoxy group; a phenoxy group; an amino group that has at least one C1-6 alkyl group as a substituent; an amino group that has at least one phenyl group as a substituent; an C 1-6 alkoxy amino group that can have at least one C 1-6 alkyl group as a substituent; a C 1-6 alkoxycarbonyl group; a C1-6 alkoxycarbonyl C1-6 alkoxy group; a C 1-6 alkylthio group; a pyrrolyl group; an imidazolyl group; a piperidyl group; a morpholino group; a pyrrolidinyl group; a thienyl group; a benzofuryl group; a piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from the group consisting of a C1-6 alkyl group, a phenyl C1-6 alkyl group, and a benzoyl group which can have at least one C1 alkyl group -6 as a substituent); a quinolyl group that can be substituted on the quinoline ring by at least one group selected from the group consisting of a C1-6 alkoxy group and an oxo group; a piperidylcarbonyl group that can be substituted on the piperidine ring by a carbostyryl group; and a triazolyl group);

(Ff5) naphthyl group that can be substituted on the naphthalene ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkoxy group unsubstituted or substituted by halogen, and an amino group that can have a group C16 alkyl as a substituent;

(Ff6) biphenyl group (which can be substituted on the biphenylyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a non-C1-6 alkoxy group substituted or substituted by halogen);

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40/854 (Ff7) fluorenyl group; pyrenyl group;

(Ff8) benzofuryl group (which can be substituted on the benzofuran ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a non-C1-6 alkoxy group substituted or substituted by halogen);

(Ff9) benzothienyl group (which can be substituted on the benzothiophene ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a non-C1-6 alkoxy group substituted or substituted by halogen);

(Ff10) pyridyl group (which can be substituted on the pyridine ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, a phenyl group (which can be substituted in the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen), a furyl group , and a thienyl group);

(Ff11) furyl group (which can be substituted on the furan ring by 1 to 3 groups selected from the group consisting of a C1-6 alkyl group, a nitro group, and a phenyl group (which can be replaced on the phenyl ring by at minus a group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a nitro group));

(Ff12) benzothiazole group (which may have at least one phenyl group on the benzothiazole ring which may have, as a substituent, a C1-6 alkoxy group on the phenyl ring);

(Ff13) thienyl group (which may have, in the thiophene ring, at least one

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41/854 group selected from the group consisting of a halogen atom, a nitro group, a C1-6 alkyl group, a pyrazolyl group that can be substituted on the pyrazole ring by at least one unsubstituted or substituted C1-6 alkyl group halogen as a substituent, and a thienyl group that may have a halogen atom in the thiophene ring);

(Ff 14) indolyl group (which can be substituted on the indole ring by at least one group selected from the group consisting of a phenyl group which can have a C1-6 alkyl group as a substituent, a C1-6 phenyl alkyl group, a alkoxycarbonyl group Ci-e, and a phenyl group);

(Ff 15) pyrrol group (which can be substituted on the pyrrole ring by at least one group selected from the group consisting of a phenyl group which can be substituted by at least one unsubstituted or halogen substituted C1-6 alkyl group, and one C1-6 alkyl group);

(Ff16) coumarila group;

(Ff17) benzimidazolyl group (which can be substituted on the benzimidazole ring by at least one thienyl group as a substituent);

(Ff18) oxazolyl group (which can be substituted on the oxazole ring by at least one phenyl group which can have a halogen atom as a substituent);

(Ff19) thiazolyl group (which can be substituted on the thiazole ring by at least one phenyl group, at least one group selected from the group consisting of a halogen atom, a nitro group, and a phenyl group);

(Ff20) quinolyl group;

(Ff21) 3,4-dihydrocarbostiryl group (which can be substituted on the 3,4 dihydrocarbostiryl ring by at least one group selected from the group consisting of a C1-6 alkoxy group, a C1-6 alkyl group, and a C1 phenyl alkoxy group -6), or carbostyryl group (which can be substituted on the ring

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42/854 carbostyryl by at least one group selected from the group consisting of a C1-6 alkoxy group, a C1-6 alkyl group, and a phenyl C1-6 alkoxy group);

(Ff22) imidazo [2,1-b] thiazolyl group;

(Ff23) imidazo [2,1-a] pyridyl group;

(Ff24) chromanyl group (which can be substituted on the chromanic ring by at least one C1-8 alkyl group); or (Ff25) 2,3-dihydrobenzofuryl group, or (Fd39) a group represented by the following general formula (Ffb):

N — R ⁴⁵ (Ffb) [0059] where R ⁴⁵ represents: a C 1-6 alkoxycarbonyl group; phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group halogen); C1-6 alkyl group substituted by amino which may have, in the amino group, a group selected from a group consisting of a phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of an atom of halogen, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) and a C1-6 alkyl group as a substituent; benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group halogen); C1-6 alkyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced with halogen); C1-6 alkoxycarbonyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted C1-6 alkyl group or

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43/854 substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen); or phenyl C2-6 alkenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a C1- alkoxy group 6 not replaced or replaced with halogen).

(F12-3) morpholino group;

(F12-4) imidazolyl group;

(F12-5) 1,4-dioxaazaospiro [4,5] decyl group (which can be substituted on the 1,4-dioxaazaespiro [4,5] decane ring by at least one oxo group as a substituent);

(F12-6) homopiperazinyl group (which can be substituted on the homopiperazine ring by at least one group selected from the group consisting of a C1-6 alkoxycarbonyl group, a C1-6 phenyl alkoxycarbonyl group, and an unsubstituted or substituted phenyl group phenyl as a substituent);

(F12-7) piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from the group consisting of an oxo group, a C1-6 alkyl group, and a phenyl C1-6 alkyl group (which can be substituted in the phenyl ring with at least one C1-6 alkyl group not substituted or substituted by halogen));

(F12-8) piperidyl group (which can be substituted on the piperidine ring by at least one oxo group as a substituent);

(F12-9) pyrrolidinyl group (which can be substituted on the pyrrolidine ring by at least one phenoxy C1-6 alkyl group which may have an unsubstituted or substituted C1-6 alkoxy group as a substituent);

(F12-10) isoindolinyl group, and (F13) in addition, R ¹⁹ and R ²⁰ can bond to each other together with nitrogen atoms adjacent to it directly or through hetero atoms, in order to form a cyclic amide or imide shown

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44/854 in any of (F13-1) to (F13-11) indicated below:

(F13-1) succinimide group;

(F13-2) oxazolidinyl group (which can be substituted on the oxazolidine ring by at least one oxo group as a substituent);

(F13-3) benzo-1,3-oxazolidinyl group (which can be substituted on the benzo-1,3-oxazolidine ring by at least one group selected from the group consisting of an oxo group, a halogen atom, and a group phenyl as a substituent);

(F13-4) imidazolidinyl group (which can be substituted on the imidazolidine ring by at least one group selected from the group consisting of an oxo group, a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from the group consisting of a halogen atom and a C1-alkoxy group), and a phenyl group);

(F13-5) benzimidazolidinyl group (which can be substituted on the benzimidazolidine ring by at least one group selected from the group consisting of: an oxo group; a halogen atom; a C1-6 alkyl group unsubstituted or substituted by halogen; one amino group that can have a C1-6 alkyl group as a substituent; a C1-6 alkoxycarbonyl group; and a piperidyl group (which can be substituted on the piperidine ring by at least one group selected from the group consisting of a C1- alkyl group 6, a phenyl group in which 1 to 3 halogen atoms can be substituted on the phenyl ring, a C1-6 alkoxycarbonyl group, and a C1-6 phenyl alkoxycarbonyl group as a substituent));

(F13-6) phthalimide group;

(F13-7) indolinyl group (which may have at least one group selected from the group consisting of a C1-6 alkyl group, a halogen atom, and an oxo group as a substituent on the indoline ring);

(F13-8) 2,3-dihydrobenzothiazolyl group (which may have at least one

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45/854 oxo group on the 2,3-dihydrobenzothiazole ring);

(F13-9) group 1 H-2,4-benzoxazinyl (which can be substituted on ring 1H-

2,4-benzoxazine by at least one oxo group as a substituent);

(F13-10) a group represented by the following general formula (Fga):

IXI [0060] where R ³⁹ represents: a hydrogen atom; a C1-6 alkyl phenyl group which may have, as a substituent, a halogen atom in the phenyl ring; C1-6 alkyl phenoxy group which may have, as a substituent, a halogen atom in the phenyl ring; C2-6 alkenyl phenyl group which may have, as a substituent, a halogen atom in the phenyl ring; phenyl group that can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen , and a phenyl group as a substituent; pyridyl group; or pyrazine group, and (F13-11) 1,3-thiazolidinyl group (which can be substituted on the 1,3thiazolidine ring by at least one group selected from a group consisting of an oxo group and a C1-6 alkylidene phenyl group that may have an unsubstituted or halogen-substituted C1-6 alkyl group on the phenyl ring as a substituent).

[0061] a group represented by the following general formula (G):

(G) non-phenyl group [0062] where R ⁴⁰ represents a C1-6 alkyl group, or substituted or substituted by halogen.

[0063] a spiro ring group represented by the following general formula (H):

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46/854

[0064] where R ⁴¹ represents:

H1) hydrogen atom;

H2) C1-8 alkyl group;

H3) phenyl C1-6 alkyl group which may have a phenyl group as a substituent on the phenyl ring;

H4) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of: a halogen atom; an unsubstituted or substituted halogen C1-6 alkyl group; an unsubstituted C1-6 alkoxy group or substituted by halogen, an amino group (which can be substituted in the amino group by at least one group selected from the group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted in the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen)); a phenoxy group (which can be substituted on the ring phenyl for at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group and piperidyl group (which can be substituted on the piperidine ring by at least one group selected from the group consisting of phenoxy groups (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom , a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent));

H5) C1-6 alkyl piperazinyl group (which can be substituted on the ring

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47/854 piperazine by at least one group selected from the group consisting of a C1-6 alkoxycarbonyl group and a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a phenyl group);

H6) C1-6 alkyl piperazinylcarbonyl group (which can be substituted on the piperazine ring by at least one group selected from the group consisting of: a C1-6 alkoxycarbonyl group; a C1-6 phenyl alkoxycarbonyl group which may have, as a substituent, a C1-6 alkyl group unsubstituted or substituted by halogen on the phenyl ring, and a phenyl C1-6 alkyl group which may have, as a substituent, at least one group selected from the group consisting of an unsubstituted C1-6 alkyl group or replaced by halogen and a phenyl group on the phenyl ring);

H7) phenylcarbamoyl C1-6 alkyl group which may have at least one C1-6 alkyl group unsubstituted or substituted by halogen as a substituent on the phenyl ring;

H8) benzoxazolyl C1-6 alkyl group (which may have at least one oxo group as a substituent on the benzoxazole ring);

H9) benzothiazolyl group;

H10) tetrazolyl group (which may have at least one phenyl group as a substituent on the tetrazole ring);

H11) C1-6 alkylsulfonyl group;

H12) phenylsulfonyl group which may have at least one C1-6 alkyl group as a substituent on the phenyl ring;

H13) phenylthiocarbamoyl group that can be substituted on the phenyl ring by at least one halogen atom as a substituent;

H14) Ci-β alkoxycarbonyl group;

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48/854

H15) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-alkoxycarbonyl group, an amino group that may have a C1 alkoxycarbonyl group -6 as a substituent, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, a nitro group, and a C1-6 alkylthio group);

H16) benzhydryloxycarbonyl group (which can be substituted on the phenyl ring by at least one halogen atom);

H17) C1-6 alkoxycarbonyl group which may have an unsubstituted or substituted phenyl phenyl group;

H18) naphthyl alkoxycarbonyl group Ci-e;

H19) C1-e alkoxycarbonyl pyridyl group;

H20) C1-6 alkoxycarbonyl group substituted by C1-6 alkoxy;

H21) C1-6 alkoxycarbonyl piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from the group consisting of a C1-6 alkoxycarbonyl group and a phenyl C1-6 alkyl group (which can have at least one atom of halogen as a substituent on the phenyl ring) as a substituent);

H22) phenoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a C1-6 alkyl group and a C1-6 alkoxy group);

H23) Ci-e alkanoyl group;

H24) benzoyl group (which can be substituted on the phenyl ring by at least one C1-6 alkyl group unsubstituted or substituted by halogen);

H25) C1-6 alkanoyl phenyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group);

H26) phenoxy C1-6 alkanoyl group (where 1 to 3 halogen atoms

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49/854 can be substituted on the phenyl ring);

H27) C2-6 alkanoyl piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from a group consisting of: a C1-6 alkanoyl group; a phenyl C1-6 alkyl group which may have, as a substituent , at least one group selected from the group consisting of a phenyl group, a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen, in the phenyl ring a C1-6 phenyl alkoxycarbonyl group which may have, as a substituent, at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1- alkoxy group 6 unsubstituted or substituted by halogen, on the phenyl ring; a phenylcarbamoyl C1-6 alkyl group that may have, as a substituent, at least one group selected from the group consisting of a halogen atom, a group C1-6 alkyl unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen, in the phenyl ring; a phenylcarbamoyl group that may have, as a substituent, at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group by halogen, in the phenyl ring; and a benzoxazolyl group);

H28) phenylcarbamoyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from the group consisting of a halogen atom, an amino group which can have a C1-6 alkyl group as a substituent, a carboxyl group, a C16 alkoxycarbonyl group, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, a piperazinyl group that may have a C1-6 alkyl group as a

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50/854 substituent on the piperazine ring, and a morpholino group);

H29) phenyl C1-6 alkylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of an unsubstituted or substituted halogen C1-6 alkyl group and an unsubstituted or substituted C1-6 alkoxy group halogen); or

H30) piperazinylcarbonyl group (which can be substituted on the piperazine ring by at least one group selected from the group consisting of a C1-6 alkoxycarbonyl group, a C1-6 phenyl alkoxycarbonyl group that can have at least one unsubstituted C1-6 alkyl group or substituted by halogen on the phenyl ring, and a phenyl C 1-6 alkyl group which may have an unsubstituted or substituted C 1-6 alkyl group on the phenyl ring).

[0065] since, in the general formula (1) above, when R ¹ represents a hydrogen atom and R ² represents a group represented by the general formula (A) above, then R ³ cannot be an isopropyl group; when R ¹ represents a hydrogen atom, R ² represents a group represented by the general formula (E) above, and m is 0, so R ¹¹ cannot be a hydrogen atom; and, in addition, when R ¹ represents a hydrogen atom and R ² represents a group represented by the general formula (F) above, then it is not possible for R ^{19 to} represent a hydrogen atom and R ^{20 to} represent a ter-butoxycarbonyl group.

[0066] Additionally, the present invention provides a 2,3-dihydro-compound

6-nitroimidazo [2,1-b] oxazole represented by the following general formula (1 '), optically active form thereof, or pharmaceutically acceptable salt thereof:

[0067] where R ¹ represents a hydrogen atom or C 1 -alkyl group, n represents an integer from 0 to 6, and R ² represents a group represented by the general formula (A ¹ ), (B ¹ ), ( C), (D ¹ ), (E ¹ ), (F ¹ ) or (G ¹ ) indicated below, and in addition, R ¹ and - (CH2) nR ² can bond together with carbon atoms

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51/854 adjacent to it by means of nitrogen atoms, in order to form a spiro ring represented by the general formula (H ') indicated below.

[0068] [0069] [0070]

General formulas of (A) - (H ') are described below as a group represented by the following general formula (A):

-OR ³ (A ') where R ³ represents:

A1) hydrogen atom;

A2) C1-8 alkyl group;

A3) C1-6 alkoxy group - C1-6 alkyl

A4) C1-6 phenyl alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a benzyloxy, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

A5) biphenylyl C1-6 alkyl group;

A6) cinamyl group;

A7) methanesulfonyl group;

A8) benzenesulfonyl group that can be replaced by a methyl group; A9) C1-8 alkanoyl group;

A10) a group represented by the general formula (Aa ') below):

N — R ⁴ (Aa ') where R ⁴ represents a C1-6 alkoxycarbonyl group, a C1-6 alkoxycarbonyl phenyl [0071] group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a benzyloxy, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen), or phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a benzyloxy, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen);

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52/854

A11) a biphenylyl alkoxycarbonyl group C1-e;

A12) 2- (2-oxo-3-benzoxazolyl) ethyl group;

A13) 2-benzoxazolyl group; or

A14) 2-phenyl-5-methyl-4-oxazolylmethyl group.

a group represented by the following general formula (B ¹ ):

-SR ⁵ (B ') [0072] where R ⁵ represents a 5- (1 H) -tetrazolyl group (where position 1 can be substituted by a C1-6 alkyl group, or unsubstituted or substituted by halogen phenyl group ), or 2-benzoxazolyl group.

[0073] a group represented by the following general formula (C):

-COOR ⁶ (C ') [0074] where R ⁶ represents a C1-6 alkyl group.

[0075] a carbamoyloxy group represented by the following general formula (D ¹ ): -OOCNR ⁷ R ⁸ (D ') [0076] where R ⁷ and R ⁸ each, in the same or different way, represents any of:

D1) hydrogen atom;

D2) C1-6 alkyl group;

D3) C1-6 alkyl group substituted by halogen;

D4) C1-6 alkoxycarbonyl group - C1-6 alkyl;

D5) Cs-s cycloalkyl group;

D6) C1-6 phenyl alkyl group (which may be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1 alkoxy group -6 not replaced or replaced by halogen);

D7) phenyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted C1-6 alkoxy group or replaced with halogen, a group

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53/854 C1-6 alkanoyl, a carboxyl group, a C1-6 alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group, a C1-6 alkylcarbamoyl group, an aminosulfonyl group, and a morpholino group);

D8) group 1-naphthyl;

D9) 4-pyridyl group; and

D10) R ⁷ and R ⁸ can bond together with nitrogen atoms adjacent to it directly or through other heteroatoms or carbon atoms, in order to form a saturated heterocyclic group shown in any of (D10-1 ) to (D10-3) indicated below, or a heterocyclic group condensed with benzene shown in any one of (D10-4) to (D10-7) indicated below:

(D10-1) a piperazinyl group represented by the general formula (Da ¹ ) below):

--h / N — R ⁹ (Da ') [0077] where R ⁹ represents:

(Da1) hydrogen atom;

(Da2) C1-8 alkyl group;

(Da3) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Da4) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted C1-6 alkoxy group or replaced with halogen);

(Da5) Ci-e alkoxycarbonyl group;

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54/854 (Da6) C1-6 phenyl alkoxycarbonyl group (which may be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen);

(Da7) 4-trifluoromethylcinamyloxycarbonyl group; or (Da8) 4-trifluoromethylbenzylideneamino group.

(D10-2) a group represented by the general formula (Db ¹ ) below:

[0078] where the dashed line represents that the bond can be a double bond, and R ¹⁰ represents:

(Db1) hydrogen atom;

(Db2) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Db3) phenoxy group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group); or (Db4) phenylamino group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group), and (D10-3) a morpholino group;

(D10-4) group 1 -indolinyl not substituted or substituted by halogen; (D10-5) 2-isoindolinyl group not substituted or substituted by halogen;

(D10-6) 1,2,3,4-tetrahydro-1-quinolinyl group not substituted or substituted by halogen; and (D10-7) unsubstituted 1,2,3,4-tetrahydro-2-isoquinolinyl group or

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55/854 [0079] replaced by halogen.

a phenoxy group represented by the general formula (E ¹ ) below:

(X) m

R where X represents a halogen atom, m represents an integer [0080] from 0 to 3, and R ¹¹ represents:

E1) hydrogen atom;

E2) C1-6 alkyl group unsubstituted or substituted by halogen;

E3) C1-6 alkoxy group unsubstituted or substituted by halogen;

E4) morpholino group;

E5) thiomorpholino group;

E6) thiomorpholino S-oxide group;

E7) group 1-imidazolyl;

E8) group 1-triazolyl;

E9) piperidini group represented by the following general formula (Ea ¹ ):

[0081] where R ¹² represents:

(Ea1) hydrogen atom;

(Ea2) Ci-e alkoxycarbonyl group; or (Ea3) phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of halogen, a cyano group, a halogen substituted C1-6 alkyl group, and a halogen substituted C1-6 alkoxy group ).

E10) a group represented by the formula (Eb ¹ ) below:

of an atom not substituted not substituted or or

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56/854

- (C = O) _k —N \ l — R ¹⁵ (Eb ') [0082] where k represents an integer of 0 or 1, and R ¹⁵ represents:

(Eb1) hydrogen atom;

(Eb2) C1-8 alkyl group;

(Eb3) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, an unsubstituted or substituted halogen C1-6 alkyl group, and a C1-6 alkoxy group unsubstituted or substituted by halogen);

(Eb4) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Eb5) Ci-e alkanoyl group;

(Eb6) C2-6 alkanoyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Eb7) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Eb8) C1-8 alkoxycarbonyl group (which can be substituted in the alkoxy group by at least one group selected from the group consisting of a halogen atom, a di (C1-6 alkyl) amino group, and an alkoxy group

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57/854

Ci-e);

(Eb9) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and a group C1-6 alkoxy not substituted or substituted by halogen);

(Eb10) C3-6 alkenyloxycarbonyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Eb11) phenoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Eb12) phenyl C1-6 alkylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Eb13) phenylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group substituted or substituted by halogen); or (Eb14) 2-benzofuranylmethyloxycarbonyl group that can be replaced by a halogen atom in the benzene ring.

E11) a group represented by the general formula (Ec ¹ ) below:

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58/854

(EC) [0083] where the dashed line represents that the bond can be a double bond, and R ¹⁶ represents:

(Ec1) hydrogen atom;

(Ec2) C1-8 alkyl group;

(Ec3) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Ec4) C1-8 alkoxycarbonyl group; or (Ec5) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and a C1-6 alkoxy group not substituted or substituted by halogen).

[0084] a group represented by the following general formula (F ¹ ):

-NR ¹⁹ R ²⁰ (F) [0085] where R ¹⁹ and R ²⁰ each, in the same or different way, represents any one of:

F1) hydrogen atom;

F2) C1-8 alkyl group;

F3) C1-6 phenyl alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1- alkoxy group 6 not substituted or substituted by halogen, and a dimethylamino group);

F4) C1-6 alkyl phenoxy group (which can be substituted on the phenyl ring by

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59/854 at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen);

F5) N-methylamino C1-6 alkyl group (where, the N position can be replaced by a C1-8 alkoxycarbonyl group, or phenyl group that can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom and a C1-6 alkyl group unsubstituted or substituted by halogen);

F6) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom and a C1-alkoxycarbonyl group);

F7) C1-6 alkoxycarbonyl group;

F8) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

F9) 4-substituted-1-piperazinylethyl group represented by the following general formula (Fa ¹ ):

--CH ₂ CH ₂ N

\ l — R ²¹

(Fa ') [0086] where R ²¹ represents a C1-8 alkoxycarbonyl group; a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, an unsubstituted or substituted halogen C1-6 alkyl group, and a C16 alkoxy group not substituted or substituted by halogen); C1-6 alkyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom and an unsubstituted or substituted C1-6 alkyl group

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60/854 halogen); or phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1- alkoxy group 6 not replaced or replaced with halogen).

F10) group 1 -substituted-4-piperidyl represented by the formula (Fb ¹ ) below:

(Fb ') [0087] where R ²² represents a C1-8 alkoxycarbonyl group; a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a C1- alkoxy group 6 not replaced or replaced by halogen); or phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1- alkoxy group 6 not replaced or replaced with halogen).

F11) 2- [4- (4-trifluoromethylphenoxy) -1-piperidinyl] ethyl group;

F12) in addition, R ¹⁹ and R ²⁰ can bond to each other together with nitrogen atoms adjacent to it directly or through other heteroatoms or carbon atoms, in order to form a heterocyclic ring shown in any of (F12- 1) to (F12-10) indicated below:

(F12-1) a group represented by the following formula (Fc ¹ ):

[0088] where the dashed line represents that the bond can be a double bond, and R ²³ represents:

(Fc1) C1-8 alkyl group;

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61/854 (Fc2) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and a C1-6 alkoxy group unsubstituted or substituted by halogen);

(Fc3) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Fc4) phenyl C1-6 alkoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fc5) 4-biphenylyl C 1-6 alkoxy group;

(Fc6) C3-6 phenyl alkenyloxy group that can be substituted on the phenyl ring by a halogen atom;

(Fc7) phenoxy group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkyl group unsubstituted or substituted by halogen, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fc8) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen);

(Fc9) Ci-e alkoxycarbonyl group;

(Fc10) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the ring

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62/854 phenyl by at least one C1-6 alkoxy group not substituted or substituted by halogen);

(Fc11) phenyl C 1-6 alkylcarbamoyl group in which a halogen atom can be substituted on the phenyl ring;

(Fc12) phenylcarbamoyl group in which a halogen atom can be substituted on the phenyl ring;

(Fc13) phenylthio group (which can be substituted on the phenyl ring by at least one C1-6 alkoxy group unsubstituted or substituted by halogen);

(Fc14) phenyl sulfoxide group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkoxy group);

(Fc15) pyridylmethoxy group; or (Fc16) a group represented by the following general formula (Fca ¹ ): _NR ²⁴ R25 (Fca ') [0089] with each of R ²⁴ and R ²⁵ representing:

(Fca1) hydrogen atom;

(Fca2) C1-8 alkyl group;

(Fca3) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fca4) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fca5) Ci-e alkanoyl group;

(Fca6) phenylacetyl group that can be substituted on the phenyl ring by a halogen atom;

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63/854 (Fca7) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1 alkoxy group -6 not replaced or replaced by halogen);

(Fca8) Ci-e alkoxycarbonyl group;

(Fca9) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a group C1-6 alkoxy not substituted or substituted by halogen);

(Fca10) phenylcarbamoyl group (which can be substituted by at least one unsubstituted C1-6 alkoxy group or substituted by halogen in the phenyl ring);

(Fca11) group 1- (4-trifluoromethylphenyl) -4-pipendinyloxycarbonyl; or (Fca12) R ²⁴ and R ²⁵ can form a piperidine ring through the nitrogen adjacent to it.

(F12-2) 4-substituted-1-piperazinyl group represented by the following general formula (Fd '):

--- 1 / N — R ²⁶ (Fd ') [0090] where R ²⁶ represents:

(Fd1) hydrogen atom;

(Fd2) C1-8 alkyl group;

(Fd3) Cs-s cycloalkyl group;

(Fd4) C5-8 cycloalkyl group - C1-8 alkyl;

(Fd5) C1-6 alkoxycarbonyl group - C1-6 alkyl;

(Fd6) cinamyl group;

(Fd7) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by de

Petition 870190039560, of 26/04/2019, p. 72/876

64/854 to 3 groups selected from the group consisting of a halogen atom; a cyan group; a C1-6 alkyl group unsubstituted or substituted by halogen; a cyclohexyl group; a C1-6 alkoxy group unsubstituted or substituted by halogen; a dimethylamino group; a C 1-6 alkoxycarbonyl group; a phenoxy group; a phenyl C 1-6 alkyl group; a styrene group; a 3-pyridyl group; a 1-imidazolyl group; and a 1-piperidine group);

(Fd8) biphenylyl methyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, a C1-6 alkoxy group not substituted or substituted by halogen, and a dimethylamino group);

(Fd9) group 1- or 2-naphthylmethyl;

(Fd10) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of: a halogen atom; a cyano group; a dimethylamino group; a C1-6 alkyl group unsubstituted or substituted by halogen; one C1-6 alkoxy group unsubstituted or substituted by halogen; a C1-6 alkoxycarbonyl group, and a carboxyl group);

(Fd11) biphenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of unsubstituted or halogen substituted C1-6 alkyl groups);

(Fd12) amino group, amino group substituted by a C1-6 alkoxycarbonyl group, benzylamino group, trifluoromethylbenzylamino group, or phenylamino group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a C1- alkyl group 6 not replaced or replaced by halogen and a halogen atom);

(Fd13) 4-chlorobenzoylmethyl group;

(Fd14) methyl phenylcarbamoyl group (which can be substituted on the phenyl ring by at least one unsubstituted or substituted C1-6 alkyl group)

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65/854 halogen);

(Fd15) 4- or 5-thiazolyl methyl group (which can be substituted on the thiazole ring by at least one group selected from the group consisting of a phenyl group unsubstituted or substituted by halogen and a C1-8 alkyl group);

(Fd16) 4-oxazolyl methyl group (which can be substituted on the oxazole ring by at least one group selected from the group consisting of an unsubstituted or halogen-substituted phenyl group and a C1-6 alkyl group);

(Fd17) 2-indolylmethyl group;

(Fd18) 2-furyl methyl group (which can be substituted on the furan ring by at least one unsubstituted or halogen-substituted phenyl group);

(Fd19) 4- or 5-imidazolyl methyl group (which can be substituted on the imidazole ring by a phenyl group);

(Fd20) 2-quinolylmethyl group;

(Fd21) group 5- (1 H) -tetrazolyl (where position 1 of the tetrazole ring can be replaced by a phenyl group);

(Fd22) 2- or 4-pyrimidine group which can be replaced by a phenyl group; (Fd23) group 2-, 3-, or 4-pyridyl;

(Fd24) 2-benzoxazolyl group;

(Fd25) 2-benzothiazolyl group;

(Fd26) 2-oxo-3-benzoxazolyl C1-6 alkyl group;

(Fd27) C2-6 alkanoyl phenoxy group that can be substituted on the phenyl ring by a halogen atom;

(Fd28) C 2-6 alkanoyl phenylthio group which can be substituted on the phenyl ring by a halogen atom;

(Fd29) C2-6 phenyl alkanoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not replaced or replaced by

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66/854 halogen);

(Fd30) benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted C1-6 alkoxy group or substituted by halogen, and a C1-8 alkylamino group);

(Fd31) 4-biphenylylcarbonyl group;

(Fd32) group 2-, 3-, or 4-pyridylcarbonyl;

(Fd33) cinnamoyl group in which a halogen atom can be substituted on the phenyl ring;

(Fd34) phenyl C 1-6 alkylsulfonyl group which can be replaced by a halogen atom in the phenyl ring;

(Fd35) benzenesulfonyl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a chlorine atom and a methyl group);

(Fd36) a group represented by the following general formula (Fda ¹ ):

-COOR ²⁷ (Fda ') [0091] where R ²⁷ represents:

(Fda1) C1-8 alkyl group not substituted or substituted by halogen;

(Fda2) Cs-s cycloalkyl group;

(Fda3) Cs-8 cycloalkyl group - C1-alkyl;

(Fda4) C1-6 alkoxy group - C1-6 alkyl;

(Fda5) C1-6 alkylamino-C1-8 alkyl group;

(Fda6) a group represented by the following general formula (Fdb ¹ ):

[0092] where R ²⁸ , R ²⁹ , or R ³⁰ represent a hydrogen atom, a C1-8 alkyl group, or a phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a group

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67/854 C1-6 alkyl unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen), respectively;

(Fda7) C1-6 phenyl alkyl group (which can be substituted on the phenyl ring by 1 to 5 groups selected from the group consisting of a halogen atom; a C1-6 alkyl group unsubstituted or substituted by halogen; an alkoxy group C1-6 unsubstituted or substituted by halogen; a C1-6 alkylthio group unsubstituted or substituted by halogen; a phenyl C1-6 alkoxy group; a hydroxy group; a methylsulfinyl group; a methanesulfonyl group; methanesulfonyloxy group; a cyano group; an acetyl group; a benzoyl group; a group, adimethoxybenzyl, an amino group, a nitro group; a carbamoyl group; an acetylamino group; a Ci-e alkoxycarbonyl group; a Ci-e alkylaminocarbonyl group; a Ci-e alkoxycarbonylamino group ; a C1-8 tri-alkylsilyl group; a pyrrolyl group; a tetrahydropyranyloxy group; and a 1-imidazolyl group);

(Fda8) biphenylyl C1-6 alkyl group;

(Fda9) benzhydryl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a halogen atom, a trifluoromethyl group, and a trifluoromethoxy group);

(Fda10) C1-6 alkyl phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a group C1-6 alkoxy not substituted or substituted by halogen);

(Fda11) group 3- (4-trifluoromethyl) phenyl-2-propynyl;

(Fda12) group 2-, 3-, or 4-pyridylmethyl;

(Fda13) a group represented by the general formula (Fdc ¹ ) below:

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68/854 [0093] where R ³¹ represents a phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a cyano group, an unsubstituted C1-6 alkyl group or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen); phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen); or benzoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced by halogen).

(Fda14) 1-piperidinoethyl group (with the 4 position of the piperidine ring being replaced by a 4-trifluoromethylphenoxy group);

(Fda15) N-methyl-N- (4-trifluoromethoxy) phenylaminoethyl group;

(Fda16) group 4- (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydro-1-pyridinylethyl;

(Fda17) group 1- or 2-naphthylmethyl;

(Fda18) group 1-, 2-, 3-, 4-, or 9-fluorenylmethyl;

(Fda19) group 2-, 3-, or 4-pyridylmethyl;

(Fda20) 2-furiI methyl group (the position 4 of the furan ring can be replaced by an unsubstituted phenyl group or substituted by halogen);

(Fda21) 3-thienylmethyl group;

(Fda22) 4-oxazolyl methyl group (the position 2 of the oxazoline ring can be replaced by a halogen atom or chlorophenyl group);

(Fda23) 4-thiazolyl methyl group that can be replaced by a halogen atom;

(Fda24) 5-oxadiazolyl methyl group with position 2 of the oxadiazoline ring being substituted by an unsubstituted phenyl group or substituted by halogen;

(Fda25) 3-pyrazolyl methyl group with position 1 of the pyrazoline ring

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69/854 can be replaced by an unsubstituted phenyl group or substituted by halogen;

(Fda26) 2- or 3-benzothiophenyl methyl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a halogen atom and an unsubstituted or substituted halogen C1-6 alkoxy group);

(Fda27) benzoxazol-2-yl methyl group that can be replaced by a halogen atom in the benzene ring;

(Fda28) 2-thienyl methyl group that can be replaced by a halogen atom;

(Fda29) 2-benzothiazolylmethyl group;

(Fda30) 2- (5-chloro) benzofuranylmethyl group;

(Fda31) 3,3-dimethyl-2-oxo-5-indolinyl methyl group (where the position 1 of the indoline ring can be replaced by a C1-8 alkyl group);

(Fda32) 2-oxo-6-benzoxazolyl methyl group (with position 1 of the benzoxazoline ring being substituted by a C1-6 alkyl group);

(Fda33) 7-chromenylmethyl group;

(Fda34) 2-oxo-1,2,3,4-tetrahydro-6-quinolyl methyl group (the position 1 of the quinoline ring being substituted by a C1-6 alkyl group);

(Fda35) 5-thiazolyl methyl group (which can be substituted on the thiazole ring by at least one group selected from the group consisting of an unsubstituted or halogen-substituted phenyl group and a C 1 -alkyl group); or (Fda36) 5- (1 H) -tetrazolyl C1-6 alkyl group (where position 1 of the tetrazole ring can be replaced by a group selected from the group consisting of an unsubstituted or halogen-substituted phenyl group and a group C1-8 alkyl).

(Fd37) a group represented by the general formula (Fe ¹ ) below:

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70/854

-Z-NR ³² R ³³ (Fe ') [0094] where Z represents -C = O or -C = S, and R ³² and R ³³ each urn, in the same or different way, represents any of:

(Fe1) hydrogen atom;

(Fe2) C1-8 alkyl group;

(Fe3) Cs-s cycloalkyl group;

(Fe4) phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fe5) C2-6 alkenyl phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C1-6 not substituted or substituted by halogen);

(Fe6) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not substituted or substituted by halogen); and (Fe7) R ³² and R ³³ can bond together with nitrogen atoms adjacent to it through other carbon atoms, to form a piperidine ring or 1,2,3,6-tetrahydropyridine ring, the position 4 of the piperidine ring or 1,2,3,6 tetrahydropyridine ring can be replaced by a phenyl group, and the phenyl group can be replaced by at least one group selected from the group consisting of a halogen atom and a group C1-6 alkyl unsubstituted or substituted by halogen, or (Fd38) a group represented by the following general formula (Ff):

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71/854

R ³⁴

-N = C \ _r 35 (Ff) [0095] where R ³⁴ represents a hydrogen atom or C 6 lower alkyl group, and R ³⁵ represents:

(Ff1) Cs-s cycloalkyl group;

(Ff2) Cs-8 cycloalkenyl group;

(Ff3) a group represented by the general formula (Ffa ¹ ) below:

(Ffa ') [0096] with each of R ³⁶ , R ³⁷ , and R ³⁸ representing: a hydrogen atom; C1-6 alkyl group; phenyl group (which can be substituted on the phenyl ring by at least 1 to 5 groups selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted C1-6 alkoxy group or substituted by halogen, a methylenedioxy group, a methanesulfonyl group, an unsubstituted or substituted C1-6 alkylthio group, a nitro group, and an acetylamino group); 2-benzofuranyl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and a non-C1-6 alkoxy group substituted or substituted by halogen); 4-biphenylyl group; 2-furyl group which can be replaced by a 4-chlorophenyl group; or 2- (4-chlorophenyl) -4-thiazolyl group.

(Ff4) phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of: a halogen atom; a C1-6 alkyl group unsubstituted or substituted by halogen; a cycloalkyl group; a hydroxy group ; a C1-8 alkoxy group unsubstituted or substituted by halogen; a Cse cycloalkoxy group; a methylenedioxy group; an ethylenedioxy group; a cyano group; a nitro group; a cinamyl group; a C1-8 alkanoyloxy group;

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72/854 C 1-6 alkanoylamino; a methanesulfonylamino group; a C 1-6 phenyl alkoxy group; a phenoxy group; a di (C1-6 alkyl) amino group; a diphenylamino group; a di (C 1-6 alkyl) amino C 1-6 alkoxy group; a methoxycarbonyl group; a C 1-6 alkoxycarbonyl C 1-6 alkoxy group; a C 1-6 alkylthio group; a pyrrolyl group; a 1-imidazolyl group; a piperidine group; a morpholino group; pyrrolidinyl group; a 2-thienyl group; a 2-benzofuranyl group; a 4-piperazinyl group with position 1 being substituted by a group selected from the group consisting of a C1-8 alkyl group, a C1-8 alkyl phenyl group, a benzoyl group, and a C1-6 alkyl substituted benzoyl group and; a 2-oxo-3 quinolyl group that can be substituted on the benzene ring by a C1-6 alkoxy group; a 4- (carbostyryl-1-yl) piperidinyl-1-carbonyl group; and a triazolyl group);

(Ff5) group 1- or 2-naphthyl substituted by a halogen atom, C 1-6 alkoxy group unsubstituted or substituted by halogen, or dimethylamino group;

(Ff6) group 3- or 4-biphenylyl (which can be substituted on the biphenyl ring by at least one group selected from the group consisting of a halogen atom, a C1-9 alkyl group unsubstituted or substituted by halogen, and a group C1-6 alkoxy not substituted or substituted by halogen);

(Ff7) 2-fluorenyl group; 3-pyrenyl group;

(Ff8) 2-benzofuranyl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1 alkoxy group -6 not replaced or replaced by halogen);

(Ff9) 2- or 3-benzothiophenyl group (which can be substituted on the benzene ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted C1-6 alkyl group or

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73/854 substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen; or the 3 or 2 position of the thiophene ring can be replaced by a C 1-6 alkyl group);

(Ff10) group 2-, 3-, or 4-pyridyl (which can be substituted on the pyridyl ring by at least one group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen , a phenyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or substituted by halogen), a 2-furyl group, a 3-furyl group, a 2-thienyl group, and a 3-thienyl group);

(Ff11) group 2- or 3-furyl (which can be substituted on the furan ring by 1 to 3 groups selected from the group consisting of a C1-6 alkyl group, a nitro group, and a phenyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a nitro group ));

(Ff12) group 2- (2-methoxyphenyl) benzothiazol-5-yl;

(Ff13) 2-thienyl group; 3-thienyl group; 4-bromo-2-thienyl group; 5chloro-2-thienyl group; 5-ethyl-2-thienyl group; 3-methyl-2-thienyl group; 5nitro-2-thienyl group; group 5- (1-methyl-3-trifluoromethyl-5-pyrazol) l) -2-thienyl;

5- (1-methyl-5-trifluoromethyl-3-pyrazolyl) -2-thienyl group; 2,2'-bitien-5ila group; 5'-bromo-2,2'-bitien-5-yl group;

(Ff14) group 1- (4-methylbenzenesulfonyl) indol-3-yl; group 1-benzylindol-3-yl; 6-methoxycarbonylindol-3-yl group; 2-phenylindol-3-yl group;

(Ff15) group 1 - (3-trifluoromethyl) phenyl-2,5-dimethyl-3-pyrrolyl;

(Ff16) 6-coumaryl group;

(Ff17) group 2- (2-thienyl) -5-benzimidazolyl; 6-benzimidazolyl group;

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74/854 (Ff18) group 2- (4-chlorophenyl) -4-oxazolyl;

(Ff19) 2-phenyl-4-thiazolyl group; 2- (4-chlorophenyl) -4-thiazolyl group; 2- (4-nitrophenyl) -4-thiazolyl group; 2- (4-biphenylyl) -4-thiazolyl group;

(Ff20) 2-thiazolyl group;

(Ff21) group 2- or 4-cholinoline;

(Ff22) 8-methoxy-3,4-dihydrocarbostyryl-5-yl group; 8-methoxy-1-methyl-3,4-dihydrocarbostyryl-5-yl group; 8-benzyloxy-3,4-dihydrocarbostyryl-5-yl group; 8-methoxycarbostyryl-5-yl group; 8-methoxy-1-methylcarbostyryl-5-yl group; 8benzyloxycarbostyryl-5-yl group; 8-methoxy-3,4-dihydrocarbostyryl-6-yl group; 8-methoxy-1-methyl-3,4-dihydrocarbostyri-6-yl group; 8-benzyloxy-3,4-dihydrocarbostyryl-6-yl group; 8-methoxycarbostyryl-6-yl group; group 8-methoxy-1methylcarbostyryl-6-yl; 8-benzyloxycarbostyryl-6-yl group;

(Ff23) 6-imidazo [2,1-b] thiazolyl group;

(Ff24) 2-imidazo [2,1-a] pyridyl group;

(Ff25) 2,2-dimethyl-6-chromanyl group; or (Ff26) 2,3-dihydro-5-benzofuranyl group.

(F12-3) morpholino group;

(F12-4) group 1-imidazolyl;

(F12-5) 1,4-dioxa-8-azospiro [4,5] -8-decyl group;

(F12-6) 4-ter-butoxycarbonyl-1-homopiperazinyl group; 4benzyloxycarbonyl-1-homopiperazinyl group; group 4- (4-biphenylyl) -1homopiperazinyl.

(F12-7) group 1-ter-butyl-2-piperazinon-4-yl; group 1- (4trifluoromethylbenzyl) -2-piperazinon-4-yl.

(F12-8) 4-oxo-1-piperidinyl group;

(F12-9) group 2- (4-trifluoromethoxyphenoxymethyl) pyrrolidin-1-yl; and (F12-10) 2-isoindolinyl group, and (F13) in addition, R ¹⁹ and R ²⁰ may bond together with nitrogen atoms adjacent to it directly or through hetero atoms, in order to form an am cyclic ida or imide shown

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75/854 in any of (F13-1) to (F13-11) indicated below:

(F13-1) group 2-succinimide;

(F13-2) 2-oxooxazolin-3-yl group;

(F13-3) 2-oxobenzo-1,3-oxazolidin-3-yl group; 5-bromo-2oxobenzo-1,3-oxazolidin-3-yl group; 5-chloro-2-oxobenzo-1,3oxazolidin-3-yl group; 5-phenyl-2-oxobenzo-1,3-oxazolidin-3-yl group;

(F13-4) 2-oxoimidazolidin-1-yl group (the position 3 of the 2oxoimidazolidin-1-yl group can be replaced by a phenyl C 1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 selected groups) the group consisting of a halogen atom and a methoxy group), or a phenyl group);

(F13-5) 2-oxobenzimidazolidin-1-yl group (which can be substituted on the benzene ring by a halogen atom, unsubstituted C1-6 alkyl group or substituted by halogen, dimethylamino group, or ethoxycarbonyl group; or 3 of the imidazolidine ring can be replaced by a 4-piperidinyl group, which can be substituted by a group selected from the group consisting of a C1-8 alkyl group, a phenyl group in which 1 to 3 halogen atoms can be substituted in the phenyl ring, a tert-butoxycarbonyl group, and a benzyloxycarbonyl group);

(F13-6) phthalimid-2-yl group;

(F13-7) ooxyindol-1-yl group, position 3 can be replaced by 2 methyl groups or fluorine atoms;

(F13-8) benzoic sulfimid-2-yl group;

(F13-9) group 1 H-2,4-benzoxazin-3 (4H) -on-4-yl;

(F13-10) a group represented by the following general formula (Fga ¹ ):

(Fga ’)

N [0097] where R ³⁹ represents: a hydrogen atom; C1-6 alkyl phenyl group

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76/854 not substituted or substituted by halogen; phenoxymethyl group unsubstituted or substituted by halogen; styrene group not substituted or substituted by halogen; phenyl group that can be substituted by at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen; biphenylyl group; 4-pyridyl group; or 2-pyrazinyl group, and (F13-11) group 5- (4-trifluoromethylbenzylidene) -1,3-thiazolidine-2,4-dion-3-yl;

[0098] a group represented by the following general formula (G ¹ ):

R ⁴⁰

[0099] where R ⁴⁰ represents a C1-6 alkyl group, or phenyl group unsubstituted or substituted by halogen.

[0100] a group of spiro ring represented by the following general formula (H '):

[0101] where R ⁴¹ represents:

H1) hydrogen atom;

H2) C1-8 alkyl group;

H3) phenyl C1-6 alkyl group or 4-biphenylyl C1-6 alkyl group;

H4) phenyl group (which can be substituted by an unsubstituted or substituted halogen C1-6 alkyl group);

H5) 4-substituted-1-piperazinyl C1-6 alkyl group (where the substituent at position 4 is a C1-6 alkoxycarbonyl group, 4biphenylylmethoxycarbonyl group or benzyloxycarbonyl group, and the benzyloxycarbonyl group can be substituted by 1 to 3 selected groups of the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a

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77/854 C1-6 alkoxy group not substituted or substituted by halogen in the benzene ring);

H6) 4-substituted-1-piperazinylcarbonyl C1-6 alkyl group, with position 4 being replaced by a C1-6 alkylcarbonyl group, 4trifluoromethylbenzyloxycarbonyl group, 4-trifluoromethylbenzyl group, or biphenylmethyl group;

H7) 4-trifluoromethylphenylcarbamoyl C1-6 alkyl group;

H8) 2-benzoxazolon-1-ylpropyl group;

H9) 2-benzothiazolyl group;

H10) 1-phenyl-5-tetrazolyl group;

H11) methanesulfonyl group;

H12) benzenesulfonyl or p-toluenesulfonyl group;

H13) phenylthiocarbamoyl group, with position 4 of the phenyl ring being substituted by a halogen atom;

H14) Ci-β alkoxycarbonyl group;

H15) a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a halogen atom, a Ci-e alkoxycarbonyl group, a Ci-e alkoxycarbonylamino group, an alkyl group C1-6 unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, a nitro group, and a methylthio group);

H16) benzhydryloxycarbonyl group (which can be replaced in the phenyl ring by 1 to 4 halogen atoms);

H17) 4-biphenylylmethoxycarbonyl group;

H18) naphthylmethoxycarbonyl group;

H19) pyridylmethoxycarbonyl group;

H20) methoxyethoxycarbonyl group;

H21) 2- (1-piperazinyl) ethoxycarbonyl group with position 4 being substituted by a C1-6 alkoxycarbonyl group, or an unsubstituted or substituted halogen phenyl C1-6 alkoxycarbonyl group;

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78/854

H22) phenoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a C1-6 alkyl group and a C1-6 alkoxy group);

H23) Ci-e alkanoyl group;

H24) benzoyl group (which can be substituted on the phenyl ring by at least one C1-6 alkyl group unsubstituted or substituted by halogen);

H25) C2-6 phenyl alkanoyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group);

H26) C2-6 alkanoyl phenoxy group (which can be replaced by 1 to 3 halogen atoms in the phenyl ring);

H27) 4-substituted-1-piperazinyl C2-6 alkanoyl group (the substituent at position 4 being a C1-6 alkanoyl group, phenyl C1-6 alkyl group, 4-biphenylethyl group, a phenyl C1-6 alkoxycarbonyl group, phenylcarbamoylmethyl group, phenyl carbamoyl group, or 2-benzoxazolyl group; and the phenyl ring of each of these phenyl C1-6 alkyl groups, a phenyl C1-6 alkoxycarbonyl group, methyl phenylcarbamoyl group and phenyl carbamoyl group, can be substituted by 1 to 3 groups selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen);

H28) phenylcarbamoyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from the group consisting of a halogen atom, a dimethylamino group, a carboxyl group, a C1-6 alkoxycarbonyl group, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, a 4-methyl-1-piperazinyl group, and a morpholino group);

H29) benzylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from the group consisting of a group

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79/854 C1-6 alkyl unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen); or

H30) 4-substituted-1-piperazinylcarbonyl group, position 4 being replaced by a ter-butoxycarbonyl group, 4trifluoromethylbenzyloxycarbonyl group, or 4-trifluoromethylbenzyl group.

[0102] since, in the general formula (1 ') above when R ¹ represents a hydrogen atom and R ² represents a group represented by the general formula (A ¹ ) above, then R ³ cannot be an isopropyl group; when R ¹ represents a hydrogen atom, R ² represents a group represented by the general formula (E ¹ ) above, and m is 0, so R ¹¹ cannot be a hydrogen atom; and, in addition, when R ¹ represents a hydrogen atom and R ² represents a group represented by the general formula (F ¹ ) above, then it is not possible that R ¹⁹ represents a hydrogen atom and R ²⁰ represents a ter-butoxycarbonyl group.

[0103] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (A).

[0104] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to general formula (1) above, where R ² represents a group represented by the general formula (B).

[0105] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt of it according to the general formula (1) above, where R ² represents a group represented by the general formula (C).

[0106] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (D).

[0107] The present invention provides 2,3-dihydro-6-nitroimidazo compound [2,1

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80/854

b] oxazole, optically active form thereof, or pharmaceutically acceptable salt thereof according to the general formula (1) above, wherein R ² represents a group represented by the general formula (E).

[0108] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to general formula (1) above, where R ² represents a group represented by the general formula (F).

[0109] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (G).

[0110] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ¹ and - (CH2) nR ² can bond together with carbon atoms adjacent to it by means of nitrogen atoms, in order to form a spiro ring represented by the general formula (H).

[0111] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt of it according to the general formula (1) above, where néOeR ² represents a group represented by any of the formulas from (A) to (G) or R ¹ and - (CFhjnR ² can bond together with carbon atoms adjacent to it through nitrogen atoms, so forming a spiro ring represented by the general formula (H).

[0112] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where n represents an integer from 1 to 6 and R ² represents a group represented by any of the formulas from (A) to (G) or R ¹ and - (CFhjnR ² can bond together with carbon atoms adjacent to the even through nitrogen atoms, in order to form

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81/854 a spiro ring represented by the general formula (H).

[0113] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ¹ represents a hydrogen atom and R ² represents a group represented by any of the formulas from (A) to (G) or R ¹ and - (ChhjnR ² can bond to each other together with carbon atoms adjacent to it for nitrogen atoms, in order to form a spiro ring represented by the general formula (H).

[0114] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole, an optically active form of the same, or a pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ¹ represents a C1-6 alkyl group and R ² represents a group represented by any of the formulas from (A) to (G) or R ¹ and - (ChhjnR ² can bond together with carbon atoms adjacent to the even by means of nitrogen atoms, in order to form a spiro ring represented by the general formula (H).

[0115] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E) and R ¹¹ represents any one of (E1) to (E3).

[0116] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E) and R ¹¹ represents (E4).

[0117] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E) and R ¹¹ represents any of (E5) to (E9).

[0118] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group

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82/854 represented by the general formula (E) and R ¹¹ represents (E10).

[0119] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E) and R ¹¹ represents (E11).

[0120] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E) and R ¹¹ represents (E12).

[0121] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to the general formula above, wherein R ² represents a group represented by the general formula (E) and R ¹¹ represents (E13).

[0122] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E) and R ¹¹ represents any of (E14) to (E17) and (E19) to (E22).

[0123] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E) and R ¹¹ represents (E18).

[0124] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F) and R ¹⁹ and R ²⁰ each, in the same or different way, represents any one of (F1) to (F11).

[0125] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to general formula (1) above, where R ² represents a group

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83/854 represented by the general formula (F) and R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, forms a heterocyclic ring shown in any of (F12-3) to (F12-10) and (F13) directly or through other heteroatoms or carbon atoms.

[0126] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F) and R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-1) directly or through other heteroatoms or carbon atoms.

[0127] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F) and R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other heteroatoms or carbon atoms.

[0128] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt of it according to the general formula (1) above, where R ² represents a group represented by the general formula (E), R ¹¹ represents (E10), and o is 0.

[0129] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt of it according to the general formula (1) above, where R ² represents a group represented by the general formula (E), R ¹¹ represents (E10), o is 1, and W represents a -CO ^- group.

[0130] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E), R ¹¹ represents (E10), o is 1, and W represents a C1-6 alkylene group.

Petition 870190039560, of 26/04/2019, p. 92/876

84/854 [0131] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E), R ¹¹ represents (E10), and R ¹⁴ is any one of (Eaa1) to (Eaa2) and (Eaa4) to (Eaa27).

[0132] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E), R ¹¹ represents (E10), and R ¹⁴ is (Eaa3).

[0133] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E), R ¹¹ represents (E11), and o is 0.

[0134] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (E), R ¹¹ represents (E11), and o is 1.

[0135] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F), R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other heteroatoms or carbon atoms and R ²⁶ is any one of (Fd1) to (Fd35), (Fd37) and (Fd39).

[0136] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to general formula (1) above, where R ² represents a group represented by the general formula (F), R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other heteroatoms or carbon atoms and R ²⁶ is (Fd36).

Petition 870190039560, of 26/04/2019, p. 93/876

85/854 [0137] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form thereof, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F), R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other hetero atoms or atoms of carbon and R ²⁶ is (Fd38). [0138] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F), R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other hetero atoms or carbon atoms, R ²⁶ is (Fd36) and R ²⁷ is any one of (Fda1) to (Fda5) and (Fda7) to (Fda34).

[0139] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F), R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other hetero atoms or carbon atoms, R ²⁶ is (Fd36) and R ²⁷ is (Fda6).

[0140] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F), R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other hetero atoms or carbon atoms, R ²⁶ is (Fd38) and R ³⁵ is any one of (Ff1) to (Ff3), (Ff5) to (Ff7), and (Ff9) to (Ff26).

[0141] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group

Petition 870190039560, of 26/04/2019, p. 94/876

86/854 represented by the general formula (F), R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other heteroatoms or carbon atoms, R ²⁶ is (Fd38) and R ³⁵ is (Ff4).

[0142] The present invention provides 2,3-dihydro-6-nitroimidazo [2,1b] oxazole compound, optically active form of the same, or pharmaceutically acceptable salt thereof according to the general formula (1) above, where R ² represents a group represented by the general formula (F), R ¹⁹ and R ²⁰ , together with nitrogen atoms adjacent to it, form a heterocyclic ring shown in (F12-2) directly or through other hetero atoms or carbon atoms, R ²⁶ is (Fd38) and R ³⁵ is (Ff8).

[0143] In the compounds represented by the general formula (1) or (T) of the present invention, particularly preferred are the following:

3- (4-trifluoromethylphenyl) -2-propenyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazine-1-carboxylate.

3- (4-trifluoromethylphenyl) -2-propenyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate.

3- (4-trifluoromethylphenyl) -2-propenyl (R) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate.

2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) pipendin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) pipendin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) piperidin-1 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [1- (4-trifluoromethoxybenzyl) pipendin-4-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [1- (4-trifluoromethoxybenzyl) pipendin-4yl] phenoxymethyl} -2,3-dihydro-imidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [1- (4-trifluoromethoxybenzyl) pipendin-4

Petition 870190039560, of 26/04/2019, p. 95/876

87/854 yl] phenoxymethyl} -2,3-dihydro-imidazo [2,1-b] oxazole.

6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) piperidin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) piperidin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(R) -6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) piperidin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [3- (4-trifluoromethoxyphenoxy) -8-azabicyclo [3.2.1] octan-8il] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole .

(S) -2-methyl-6-nitro-2- {4- [3- (4-trifluoromethoxyphenoxy) -8azabicyclo [3.2.1] octan-8-yl] phenoxymethyl} -2,3-dihydroimidazo [2,1 -b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [3- (4-trifluoromethoxyphenoxy) -8azabicyclo [3.2.1] octan-8-yl] phenoxymethyl} -2,3-dihydroimidazo [2,1 -b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [3- (4-trifluoromethoxyphenoxy) -8azabicyclo [3.2.1] octan-8-yl] phenoxymethyl} -2,3-dihydroimidazo [2,1 -b] oxazole 4 toluene sulfonate.

2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzylidenoamino) piperazin-1-yl] -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzylidenoamino) piperazin-1-yl] -

2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzylidenoamino) piperazin-1-yl] -

2,3-dihydroimidazo [2,1-b] oxazole.

2- [4- (5-chlorobenzofuran-2-ylmethyleneamino) piperazin-1-yl] -2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazole.

(S) -2- [4- (5-chlorobenzofuran-2-ylmethyleneamino) piperazin-1-yl] -2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2- [4- (5-chlorobenzofuran-2-ylmethyleneamino) piperazin-1-yl] -2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazole.

2- [4- (5-trifluoromethylbenzofuran-2-ylmethyleneamino) piperazin-1-yl] -2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazole.

Petition 870190039560, of 26/04/2019, p. 96/876

88/854 (S) -2- [4- (5-trifluoromethylbenzofuran-2-ylmethyleneamino) piperazin-1-yl] -2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2- [4- (5-trifluoromethylbenzofuran-2-ylmethyleneamino) piperazin-1-yl] -2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylbenzyl) piperazin-1-yl] phenoxymethyl} -2,3dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylbenzyl) piperazin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylbenzyl) piperazin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxybenzyl) piperazin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxybenzyl) piperazin-1yl] phenoxymethyl} -2,3-dihydro-imidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxybenzyl) piperazin-1yl] phenoxymethyl} -2,3-dihydro-imidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- [4- (4-trifluoromethylphenoxy) -pipendin-1-ylmethyl] -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- [4- (4-trifluoromethylphenoxy) pipendin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- [4- (4-trifluoromethylphenoxy) pipendin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole.

2- [4- (4-trifluoromethoxyphenyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole.

(S) -2- [4- (4-trifluoromethoxyphenyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole.

(R) -2- [4- (4-trifluoromethoxyphenyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole.

2- [4- (4-chlorophenyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole.

Petition 870190039560, of 26/04/2019, p. 97/876

89/854 (S) -2- [4- (4-chlorophenyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole.

(R) -2- [4- (4-chlorophenyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- [4- (4'-trifluoromethylbiphenyl-4-ylmethyl) piperazin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- [4- (4'-trifluoromethylbiphenyl-4-ylmethyl) piperazin-1-ylmethyl] -

2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- [4- (4'-trifluoromethylbiphenyl-4-ylmethyl) piperazin-1-ylmethyl] -

2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylphenyl) -piperazin-1-yl] phenoxymethyl} -2,3dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylphenyl) -piperazin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylphenyl) -piperazin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (4-chlorobenzyl) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (4-chlorobenzyl) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-chlorobenzyl) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (4-chlorophenyl) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (4-chlorophenyl) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-chlorophenyl) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxybenzyloxycarbonyl) piperazin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole.

Petition 870190039560, of 26/04/2019, p. 98/876

90/854 (S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxy-benzyloxycarbonyl) piperazin-1 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxy-benzyloxycarbonyl) piperazin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (3,4-dichlorobenzyloxy-carbonyl) piperazin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (3,4-dichlorobenzyloxy-carbonyl) piperazin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (3,4-dichlorobenzyloxy-carbonyl) piperazin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- [4- (4-trifluoromethoxyphenoxy) -piperidin-1-ylmethyl] -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- [4- (4-trifluoromethoxyphenoxy) -piperidin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- [4- (4-trifluoromethoxyphenoxy) -piperidin-1-ylmethyl] -2,3 dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- [4- (4-trifluoromethylphenyl) -piperazin-1-ylmethyl] -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- [4- (4-trifluoromethylphenyl) -piperazin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- [4- (4-trifluoromethylphenyl) -piperazin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- [4- (5-trifluoromethoxybenzofuran-2ylmethyleneamino) piperazin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- [4- (5-trifluoromethoxy-benzofuran-2ylmethyleneamino) piperazin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- [4- (5-trifluoromethoxy-benzofuran-2ylmethyleneamino) piperazin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- [4- (5-trifluoromethylbenzofuran-2ylmethyleneamino) piperazin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole.

Petition 870190039560, of 26/04/2019, p. 99/876

91/854 (S) -2-methyl-6-nitro-2- [4- (5-trifluoromethylbenzofuran-2ylmethyleneamino) piperazin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- [4- (5-trifluoromethylbenzofuran-2ylmethyleneamino) piperazin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (4-chlorophenoxy) piperidin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (4-chlorophenoxy) piperidin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-chlorophenoxy) piperidin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylphenoxy) -pipendin-1-yl] phenoxymethyl} -2,3dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylphenoxy) piperidin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

(R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylphenoxy) pipendin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole.

2-methyl-6-nitro-2- {4- [1- (4-chlorobenzyl) piperidin-4-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole.

(S) -2-methyl-6-nitro-2- {4- [1- (4-chlorobenzyl) piperidin-4-yl] phenoxymethyl} -2,3dihydroimidazo [2,1-b] oxazole, or (R) -2-methyl-6-nitro-2- {4- [1- (4-chlorobenzyl) piperidin-4-yl] phenoxymethyl} -2,3dihydroimidazo [2,1-b] oxazole.

[0144] The present invention provides a pharmaceutical composition which is an antituberculous agent comprising, as an active ingredient, the 2,3-dihydro-6-nitroimidazo [2,1-b] oxazole compound, its optically active form, or its pharmacologically salt. acceptable represented by the general formula (1) or (T).

[0145] In particular, the present invention provides a pharmaceutical composition that is an antituberculous agent comprising, as an active ingredient, at least one compound selected from the 2,3-dihydro-6nitroimidazo [2,1-b] oxazole compounds that are preferred compound listed above.

Petition 870190039560, of 26/04/2019, p. 100/876

92/854 [0146] The present invention provides a method for producing a compound represented by the following general formula (1a):

(1a) [0147] wherein R ¹ , R ^{2 and} n are defined as in claim 1.

[0148] and said production method comprises: the reaction of a 4-nitroimidazole compound represented by the following general formula (2):

H

[0149] where Xi represents a halogen atom or nitro group, with an epoxy compound represented by the following general formula (3a):

(3a) [0150] wherein R ¹ , R ^{2 and} n are defined as in claim 1, in order to obtain a compound represented by the following general formula (4a):

(4a) [0151] wherein R ¹ , R ^{2 and} n are defined as in claim 1, and Xi represents a halogen atom or nitro group; and the following ring closure of the compound obtained represented by the general formula (4a) above.

[0152] The present invention provides a method for producing a compound

Petition 870190039560, of 26/04/2019, p. 101/876

93/854 represented by the following general formula (1b):

[0153] wherein R ¹ is as defined in claim 1, and R ^2a represents a group represented by the general formula (A), (B), (E) or (F) according to claim 1.

[0154] being that said method of production comprises: the reaction of a compound represented by the general formula (3b) below:

R ¹

[0155] where R ¹ is as defined in claim 1, and Xi represents a halogen atom or nitro group, [0156] with a compound (5) represented by the following general formula R ^2a H (5) or salt.

wherein R ^2a represents the group represented by the general formula (A), (B), (F) according to claim 1, in order to obtain a compound of its [0157] (E) or represented by the general formula ( 4b) as follows:

(4b) [0158] wherein R ¹ is as defined in claim 1, R ^2a represents the group represented by the general formula (A), (B), (E) or (F) according to claim 1, and Xi represents a halogen atom or nitro group; and

Petition 870190039560, of 26/04/2019, p. 102/876

94/854 [0159] the following ring closure of the compound obtained represented by the general formula (4b) above.

[0160] The present invention provides a method for producing a compound represented by the following general formula (1c):

(1c) wherein R ⁴¹ is as defined in claim 1. said production method comprising: the reaction of a [0161] [0162] compound represented by the following general formula (2):

H

N

N (2)

The ₂ N [0163] where Xi represents a halogen atom or nitro group, with a compound represented by the following general formula (3c):

N — R ⁴¹ (3c) [0164] [0165] follow:

wherein R ⁴¹ is as defined in claim 1.

in order to obtain a compound represented by the general formula (4c) to

(4c) [0166] o ₂ n where R ⁴¹ is as defined in claim 1, and Xi represents an atom

Petition 870190039560, of 26/04/2019, p. 103/876

95/854 halogen or nitro group; and [0167] the following ring closure of the obtained compound represented by the general formula (4c) above.

Best way to carry out the invention [0168] In this description, each group represented by R ¹ , R ² , R ³ or similar is specifically as follows:

[0169] Examples of halogen atoms are, for example, fluorine atom, chlorine atom, bromine atom and iodine atom.

[0170] A C1-6 alkyl group is a straight or branched alkyl group containing 1 to 6 carbon atoms, examples of which include a methyl group, ethyl group, n-propyl group, isopropyl group, n group -butyl, isobutyl group, ter-butyl group, sec-butyl group, n-pentyl group, neopentyl group, nhexyl group, isohexyl group, 3-methylpentyl group or the like.

[0171] A C1-6 alkylene group is a straight or branched alkylene group containing from 1 to 6 carbon atoms, examples of which include a methylene group, ethylene group, trimethylene group, 2-methylthmethylene group, group 2 , 2dimethylthmethylene, 1-methyltrimethylene group, methylmethyl group, ethylmethyl group, tetramethylene group, pentamethylene group, hexamethylene group or the like.

[0172] A C1-6 alkoxy group is a group containing a C1-6 alkyl group, as defined above, and an oxygen atom, examples of which include a methoxy group, ethoxy group, n-propoxy group, group isopropoxy, n-butoxy group, isobutoxy group, ter-butoxy group, sec-butoxy group, n-pentoxy group, neopentoxy group, n-hexyloxy group, isohexoxy group, 3-methylpentoxy group or the like.

[0173] A C1-6 alkoxy group - C1-6 alkyl is a group containing a C1-6 alkyl group and the C1-6 alkoxy group described above, examples of which include a methoxymethyl group, 2-methoxyethyl group, group 3-methoxypropyl, 4-methoxybutyl group, 5-methoxypentyl group, 6-methoxyxy group, ethoxymethyl group, 2-ethoxyethyl group, 3-ethoxypropyl group, 2-isopropoxyethyl group, ter-butoxymethyl group, 2- (terbutoxy) ethyl group, group 3- (ter-butoxy) propyl, group 6- (ter-butoxy) hexyl, group 4- (terbutoxy) butyl or similar.

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96/854 [0174] A C1-6 alkyl group unsubstituted or substituted by halogen is a straight or branched alkyl group containing 1 to 6 carbon atoms, as defined above, and optionally substituted by 1 to 7 carbon atoms halogen, examples of which include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, ter-butyl group, sec-butyl group, n-pentyl group, neopentyl group, group n-hexyl, isohexyl group, 3-methylpentyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, dichlorofluoromethyl group, 2,2,2-trifluoroethyl group , 2-chloroethyl group, 3,3,3-trifluoropropyl group, heptafluoropropyl group, heptafluoroisopropyl group, 3-chloropropyl group, 2-chloropropyl group, 3-bromopropyl group, 4,4,4trifluorobutyl group, group 4,4,4, 3,3-pentafluorobutyl, gru po 4-chlorobutyl, 4bromobutyl group, 2-chlorobutyl group, 5,5,5-trifluoropentyl group, 5-chloropentyl group, 6,6,6-trifluorohexyl group, 6-chlorohexyl group or the like.

[0175] A C1-6 alkoxy group unsubstituted or substituted by halogen is a C1-6 alkoxy group, as defined above, and an alkoxy group substituted by 1 to 7 halogen atoms, examples of which include a methoxy group , ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, ter-butoxy group, sec-butoxy group, n-pentoxy group, neopentoxy group, n-hexyloxy group, isohexyloxy group, 3-methylpentoxy group , fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, chloromethoxy group, dichloromethoxy group, trichloromethoxy group, bromomethoxy group, dibromomethoxy group, dichlorofluoromethoxy group, 2,2,2trifluoroethoxy group, pentafluoroethoxy group 3, 2-group trifluoropropoxy, heptafluoropropoxy group, heptafluoroisopropoxy group, 3-chloropropoxy group, 2-chloropropoxy group, 3-bromopropoxy group, 4,4,4,3-trifluorobutoxy group, 4,4,4,3,3 pentafluorobutoxy group, 4-chlorobutoxy group, 4-chlorobutoxy group obutoxy, 2-chlorobutoxy group, 5,5,5-trifluoropentoxy group, 5-chloropentoxy group, 6,6,6-trifluoroexyloxy group, 6 chlorohexyloxy group or the like.

[0176] Examples of a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a group

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97/854 phenyl C1-6 alkoxy; a C1-6 alkyl group unsubstituted or substituted by halogen; a C1-6 alkoxy group unsubstituted or substituted by halogen; and phenoxy group which can have at least one C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent on the phenyl ring) include a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 selected groups a group consisting of a phenyl C1-6 alkoxy group, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a phenoxy group that may have from 1 to 3 a C1-6 alkoxy groups unsubstituted or substituted by halogens as a substituent on the phenyl ring), for example, a benzyl group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group, 2-phenylpropyl group, group 4 -phenylbutyl, 5-phenylpentyl group, 4-phenylpentyl group, 6-phenylexyl group, 2-benzyloxybenzyl group, 3-benzyloxybenzyl group, 4benzyloxybenzyl group, 2,4-dibenzyloxybenzyl group, 2,4,6-tribenyloxybenzyl group, group 2 ( 2-phenethyloxy) benzyl, group 3 - (2-phenethyloxy) benzyl, group 4- (2-phenethyloxy) benzyl, group 2- (3-phenylpropoxy) benzyl, group 3- (3-phenylpropoxy) benzyl, group 4- (3-phenylpropoxy) benzyl, group 2- ( 4-phenylbutoxy) benzyl, group 3- (4-phenylbutoxy) benzyl, group 4- (4-phenylbutoxy) benzyl, group 2- (5-phenylpentyloxy) benzyl, group 3- (5phenylpentyloxy) benzyl, group 4- (5- phenylpentyloxy) benzyl, group 2- (6-phenylexyloxy) benzyl, group 3- (6-phenylexyloxy) benzyl, group 4- (6-phenylexyloxy) benzyl, group 2-methylbenzyl, group 2,3-dimethylbenzyl, group 3,4 -dimethylbenzyl, group 3,5-dimethylbenzyl, group 2,6dimethylbenzyl, group 2,4-dimethylbenzyl, group 2,5-dimethylbenzyl, group 2,4,6trimethylbenzyl, group 3,5-ditrifluoromethylbenzyl, group 2,4,6- trifluoromethylbenzyl, 2-trifluoromethylbenzyl group, 3-trifluoromethylbenzyl group, 4trifluoromethylbenzyl group, 2-trifluoromethoxybenzyl group, 3-trifluoromethoxybenzyl group, 3-trifluoromethoxybenzyl group, 3-trifluoromethoxybenzyl group, group 3 zila, 3,5-dimethoxybenzyl group, 2,6-dimethoxybenzyl group, 2,4-dimethoxybenzyl group, 2,5-dimethoxybenzyl group, 2,4,6-trimethoxybenzyl group, 2,6-ditrifluoromethoxybenzyl group, group 2,3 , 4-trifluoromethoxybenzyl, group 1- (4-benzyloxyphenyl) ethyl, group 1 - (3-benzyloxyphenyl) ethyl, group 1 - (2-benzyloxyphenyl) ethyl, group 1 - (2-trifluoromethylphenyl) ethyl, group 1 - (3-trifluoromethylphenyl) ) ethyl, group 1- (4

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98/854 trifluoromethylphenyl) ethyl, group 1- (2-trifluoromethoxyphenyl) ethyl, group 1- (3-trifluoromethoxyphenyl) ethyl, group 1- (4-trifluoromethoxyphenyl) ethyl, group 2- (4-benzyloxyphenyl) ethyl, group 2- (3-benzyloxyphenyl) ethyl ) ethyl, group 2- (2-benzyloxyphenyl) ethyl, group

2- (2-trifluoromethylphenyl) ethyl, group 2- (3-trifluoromethylphenyl) ethyl, group 2- (4- trifluoromethylphenyl) ethyl, group 2- (2-trifluoromethoxyphenyl) ethyl, group 2- (3- trifluoromethoxyphenyl) ethyl, group 2- (3-trifluoromethoxyphenyl) ethyl, group 3- (4- benzyloxyphenyl) propyl, group 3- (3-benzyloxyphenyl) propyl, group 3- (2- benzyloxyphenyl) propyl, group 3- (2-trifluoromethylphenyl) propyl, group 3- (3- trifluoromethylphenyl) propyl, group 3- (4-trifluoromethylphenyl) propyl, group 3- (2- trifluoromethoxyphenyl) propyl, group 3- (3-trifluoromethoxyphenyl) propyl, group 3- (4- trifluoromethoxyphenyl) propyl, group 4- (3-trifluoromethylphenyl) butyl, group 5- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethoxyphenyl) pentyl, group 6- (3-trifluoromethylphenyl) hexyl, group 6- (4-

trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethoxyphenyl) hexyl, group 2-phenoxybenzyl, group 3-phenoxybenzyl, group 4-phenoxybenzyl, group 2,5-diphenoxybenzyl, group 2,4,6triphenoxybenzyl, group 1- (4-phenoxyphenyl) ) ethyl, group 1- (3-phenoxyphenyl) ethyl, group 1- (2-phenoxyphenyl) ethyl, group 3- (4-phenoxyphenyl) propyl, group 3- (3-phenoxyphenyl) propyl, group 3 (2-phenoxyphenyl) propyl, group 2- (4-trifluoromethoxyphenoxy) benzyl, group 3- (4-trifluoromethoxyphenoxy) benzyl, group 4- (4-trifluoromethoxyphenoxy) benzyl, group 1- (4- (4trifluoromethoxyphenoxy) phenyl) ethyl, group 1- (3- (4- trifluoromethoxyphenoxy) phenyl) ethyl, group 1 (2- (4-trifluoromethoxyphenoxy) phenyl) ethyl, group 3- (4- (4-trifluoromethoxyphenoxy) phenyl) propyl, group 3- (3- (4-trifluoromethoxyphenoxy) phenyl) propyl, group 3- (2- (4trifluoromethoxyphenoxy) phenyl) propyl, group 2-trifluoromethyl-3-trifluoromethoxybenzyl, group 2-benzyloxy-3-trifluoromethoxybenzyl, group 3-phenoxy-4-trifluoromethylbenzyl or similar.

[0177] Examples of a biphenylyl C1-6 alkyl group include the phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of a phenyl C1-6 alkoxy group, an alkyl group C1-6 unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen and a phenoxy group that may have at least one C1-6 alkoxy group

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99/854 unsubstituted or substituted by halogen as a substituent on the phenyl ring), by

example, a group 2-biphenylylmethyl, group 2- (2-biphenylyl) ethyl, group 3- (2- biphenylyl) propyl, group 4- (2-biphenylyl) butyl, group 5- (2-biphenylyl) pentyl, group 6- (2- biphenylyl) hexyl, group 3-biphenylmethyl, group 2- (3-biphenylyl) ethyl, group 3- (3- biphenylyl) propyl, group 4- (3-biphenylyl) butyl, group 5- (3-biphenylyl) pentyl, group 6- (3- biphenylyl) hexyl, group 4-biphenylmethyl, group 2- (4-biphenylyl) ethyl, group 3- (4- biphenylyl) propyl, group 4- (4-biphenylyl) butyl, group 5- (4-biphenylyl) pentyl, group 6- (4-

biphenylyl) hexyl or the like.

[0178] A phenyl C2-6 alkenyl group is a group containing a phenyl group and an alkenyl group having 2 to 6 carbon atoms and 1 to 3 double bonds. These groups can be found in the trans or cis form and both forms are of course included. For example, a 3-phenyl-2-propenyl group (common name: cinamyl group), 4-phenyl-2-butenyl group, 4-phenyl-3-butenyl group, 5-phenyl-4-pentenyl group, group 5 -phenyl-3-pentenyl, 6-phenyl-5-hexenyl group, 6-phenyl-4hexenyl group, 6-phenyl-3-hexenyl group, 4-phenyl-1,3-butadienyl group, 6-phenyl-1 group, 3,5hexatrienila or similar.

[0179] A C1-6 alkylsulfonyl group is a group containing an alkyl group containing from 1 to 6 carbon atoms and a sulfonyl group, examples of which include a methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, pentanesulfonyl group , hexanesulfonyl group or the like.

[0180] Examples of a benzene sulfonyl group that can be substituted by a C1-6 alkyl group include a benzenesulfonyl group that can be substituted by 1 to 3 C1-6 alkyl groups, for example, a benzene sulfonyl group, otoluenesulfonyl group, m-toluenesulfonyl group, p-toluenesulfonyl group, 2-ethylbenzenesulfonyl group, 3-ethylbenzenesulfonyl group, 4-ethylbenzenesulfonyl group, 2-propylbenzenesulfonyl group, 3-propylbenzenesulfonyl group, 2-propylbenzenesulfonyl group, 2-benzylbenzenesulfonyl group , 4,6-trimethylbenzenesulfonyl or the like.

[0181] A C1-6 alkanoyl group is a group derived from a carboxylic acid

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100/854 aliphatic containing from 1 to 6 carbon atoms, examples of which include a formyl group, acetyl group, propionyl group, butyryl group, pentanoyl group, hexanoyl group or the like.

[0182] A C1-6 alkoxycarbonyl group is a group containing a C1-6 alkoxy group, as defined above, and a carbonyl group, examples of which include a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isoproxycarbonyl group, n group -butoxycarbonyl, isobutoxycarbonyl group, terbutoxycarbonyl group, sec-butoxycarbonyl group, n-pentoxycarbonyl group, neopentoxicarbonyl group, n-hexyloxycarbonyl group, isohexyloxycarbonyl group, 3methylpentoxicarbonyl group or similar.

[0183] A C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a C1-6 phenyl alkoxy group, an unsubstituted or substituted C1-6 alkyl group , and a C1-6 alkoxy group unsubstituted or substituted by halogen) is a group containing a phenyl C1-6 alkoxy group that can be substituted on the phenyl ring, as defined above, by 1 to 3 groups selected from a group consisting of a phenyl C1-6 alkoxy group, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen and a carbonyl group, examples of which include a benzyloxycarbonyl group, group 1-phenylethoxycarbonyl, group 2-phenylethoxycarbonyl, group 3-phenylpropoxycarbonyl, group 2-phenylpropoxycarbonyl, group 4-phenylbutoxycarbonyl, group 5-phenylpentoxicarbonyl, group 4-phenylpentoxicarbonyl, group 6-phenylexyloxycarbonyl, 2benzyloxybenzyloxycarbonyl group, 3-benzyloxybenzyloxycarbonyl group, 4benzyloxybenzyloxycarbonyl group, 2,4-dibenzyloxybenzyloxycarbonyl group, 3,4,5benzyloxybenzyloxycarbonyl group, 2-trifluoromethylbenzyloxycarbonyl group, 2-trifluoromethylbenzyloxycarbonyl group, 3methylbenzyl group , 4,6 trimethylbenzyloxycarbonyl, 2,3-ditrifluoromethylbenzyloxycarbonyl group, 2,4,6 tri (trifluoromethyl) benzyloxycarbonyl group, 2-methoxybenzyloxycarbonyl group, group 3 methoxybenzyloxycarbonyl, group 4-methoxybenzyloxycarbonyl, group 2,4

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101/854 dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl group, 2,5ditrifluoromethoxybenzyloxycarbonyl group, 2,4,6-tri (tnfluoromethoxy) benzyloxycarbonyl group, 3-trifluoromethylbenzyloxycarbonyl group, 4-trifluoromethylbenzoxycarbonyl group, 3-trifluoromethylbenzyloxycarbonyl group trifluoromethoxybenzyloxycarbonyl, group 4trifluoromethoxybenzyloxycarbonyl, group 2- (2-trifluoromethylphenyl) ethoxycarbonyl, group 2 (3-trifluoromethylphenyl) ethoxycarbonyl, group 2- (4-trifluoromethylphenyl) ethoxycarbonyl, group

2- (2-trifluoromethoxyphenyl) ethoxycarbonyl, group 2- (3-trifluoromethoxyphenyl) ethoxycarbonyl, group 2- (4-trifluoromethoxyphenyl) ethoxycarbonyl, group 3- (4benzyloxyphenyl) propoxycarbonyl, group 3- (3-benzyloxyphenyl) propoxycarbonyl group (2benzyloxyphenyl) propoxycarbonyl, group 3- (2-trifluoromethylphenyl) propoxycarbonyl, group

3- (3-trifluoromethylphenyl) propoxycarbonyl, group 3- (4-trifluoromethylphenyl) propoxycarbonyl, group 3- (2-trifluoromethoxyphenyl) propoxycarbonyl, group 3- (3trifluoromethoxyphenyl) propoxycarbonyl, group 3- (4-trifluoromethoxycarbonyl) group (3-benzyloxyphenyl) butoxycarbonyl, group 4- (4-benzyloxyphenyl) butoxycarbonyl, group 4- (3-trifluoromethylphenyl) butoxycarbonyl, group 4- (4trifluoromethylphenyl) butoxycarbonyl, group 5- (3-benzyloxyphenyl) pentoxycarbonyl, group 5 ( benzyloxyphenyl) pentoxycarbonyl, group 5- (4-trifluoromethylphenyl) pentoxycarbonyl, group 4- (4-trifluoromethylphenyl) pentoxycarbonyl, group 4- (4trifluoromethoxyphenyl) pentoxycarbonyl, group 6- (3-benzyloxyphenyl) benzyloxycarbonyl, group 6- (3-benzyloxyphenyl) hexyloxycarbonyl hexyloxycarbonyl, group 6- [3- (2-phenethyloxy) phenyl] hexyloxycarbonyl, group 6- [4- (2-phenethyloxy) phenyl] hexyloxycarbonyl, group 6- [3- (3-phenylpropoxy) phenyl] hexyloxycarbonyl, group 6- [4 - (4-phenylbutoxy) phenyl] hexyloxycarbonyl, group 6- [4- (5-phenylpentyloxy) phenyl] hexyloxy bonila, group 6- [4- (6phenylexyloxy) phenyl] hexyloxycarbonyl, group 6- (3-trifluoromethylphenyl) hexyloxycarbonyl, group 6- (4-trifluoromethylphenyl) hexyloxycarbonyl, group 6- (4trifluoromethoxyphenyl) hexyloxycarbonyl, group 2-tribyldyl 3-trifluoromethoxy-5-benzyloxybenzyloxycarbonyl group, 2-trifluoromethyl-3-trifluoromethoxybenzyloxycarbonyl group or the like.

[0184] Examples of a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a group

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102/854 phenyl C1-6 alkoxy, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) include a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of a phenyl C1-6 alkoxy group, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), for example, a group benzyl, group 1-phenethyl, group 2-phenethyl, group 3-phenylpropyl, group 2-phenylpropyl, group 4-phenylbutyl, group 5-phenylpentyl, group 4-phenylpentyl, group 6-phenylexyl, group 2-benzyloxybenzyl, group 3-benzyloxybenzyl, group 4-benzyloxybenzyl, group 2,4-dibenzyloxybenzyl, group 2,4,6-tribenzyloxybenzyl, group 2- (2-phenethyloxy) benzyl, group 3- (2-phenethyloxy) benzyl, group 4- (2-phenethyloxy) benzyl, group 2- (3-phenylpropoxy) benzyl, group 3- (3-phenylpropoxy) benzyl, group 4- (3-phenylpropoxy) benzyl la, group 2- (4-phenylbutoxy) benzyl, group 3- (4-phenylbutoxy) benzyl, group 4- (4-phenylbutoxy) benzyl, group 2- (5-phenylpentyloxy) benzyl, group 3- (5-phenylpentyloxy) benzyl, group 4- (5-phenylpentyloxy) benzyl, group 2- (6-phenylexyloxy) benzyl, group 3- (6-phenylexyloxy) benzyl, group 4- (6-phenylexyloxy) benzyl, group 2-methylbenzyl, group 2,3-dimethylbenzyl, 3,4-dimethylbenzyl group, 3,5-dimethylbenzyl group, 2,6-dimethylbenzyl group, 2,4-dimethylbenzyl group, 2,5dimethylbenzyl group, 2,4,6-trimethylbenzyl group, 3,5-ditrifluoromethylbenzyl group, group 2, 4,6-trifluoromethylbenzyl, group 2-trifluoromethylbenzyl, group 3-trifluoromethylbenzyl, group 4-trifluoromethylbenzyl, group 2-trifluoromethoxybenzyl, group 3trifluoromethoxybenzyl, group 4-trifluoromethoxybenzyl, group 4

2,3-dimethoxybenzyl, group 3,4-dimethoxybenzyl, group 3,5-dimethoxybenzyl, group 2,6 dimethoxybenzyl, group 2,4-dimethoxybenzyl, group 2,5-dimethoxybenzyl, group 2,4,6trimethoxybenzyl, group 2, 6-ditrifluoromethoxybenzyl, group 2,3,4-trifluoromethoxybenzyl, group 1- (4-benzyloxyphenyl) ethyl, group 1- (3-benzyloxyphenyl) ethyl, group 1- (2-benzyloxyphenyl) ethyl, group 1 - (2-trifluoromethylphenyl) ethyl , group 1- (3trifluoromethylphenyl) ethyl, group 1 - (4-trifluoromethylphenyl) ethyl, group 1- (2trifluoromethoxyphenyl) ethyl, group 1- (3-trifluoromethoxyphenyl) ethyl, group 1- (4trifluoromethoxyphenyl) ethyl, group 2- (4 -benzyloxyphenyl) ethyl, group 2- (3-benzyloxyphenyl) ethyl, group 2- (2-benzyloxyphenyl) ethyl, group 2- (2-trifluoromethylphenyl) ethyl, group 2- (3Petition 870190039560, from 26/04/2019, page 111/876

103/854

trifluoromethylphenyl) ethyl, group 2- (4-trifluoromethylphenyl) ethyl, group 2- (2- trifluoromethoxyphenyl) ethyl, group 2- (3-trifluoromethoxyphenyl) ethyl, group 2- (3- trifluoromethoxyphenyl) ethyl, group 3- (4-benzyloxyphenyl) propyl, group 3- (3- benzyloxyphenyl) propyl, group 3- (2-benzyloxyphenyl) propyl, group 3- (2- trifluoromethylphenyl) propyl, group 3- (3-trifluoromethylphenyl) propyl, group 3- (4- trifluoromethylphenyl) propyl, group 3- (2-trifluoromethylphenyl) propyl, group 3- (3- trifluoromethoxyphenyl) propyl, group i 3- (4-trifluoromethoxyphenyl) propyl, group 4- (3- trifluoromethylphenyl) butyl, group 5- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethoxyphenyl) pentyl, group 6- (3- trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethylphenyl) hexyl, group 6- (4- trifluoromethoxyphenyl) hexyl, group 2-trifluoromethyl-3-tnfluoromethoxybenzyl, group 2-

benzyloxy-3-trifluoromethoxybenzyl, 3-phenoxy-4-trifluoromethylbenzyl group or the like. [0185] A C1-6 biphenylyl alkoxycarbonyl group includes, for example, a 2biphenylylmethoxycarbonyl group, 2- (2-biphenylyl) ethoxycarbonyl, group 3- (2-

biphenylyl) propoxycarbonyl, group 4- (2-biphenylyl) butoxycarbonyl, group 5- (2- biphenylyl) pentoxycarbonyl, group 6- (2-biphenylyl) hexyloxycarbonyl, group 3- biphenylmethoxycarbonyl, group 2- (3-biphenylyl) ethoxycarbonyl, group 3- (3- biphenylyl) propoxycarbonyl, group 4- (3-biphenylyl) butoxycarbonyl, group 5- (3- biphenylyl) pentoxycarbonyl, group 6- (3-biphenylyl) hexyloxycarbonyl, group 4- biphenylmethoxycarbonyl, group 2- (4-biphenylyl) ethoxycarbonyl, group 3- (4- biphenylyl) propoxycarbonyl, group 4- (4-biphenylyl) butoxycarbonyl, group 5- (4-

biphenylyl) pentoxycarbonyl, group 6- (4-biphenylyl) hexyloxycarbonyl or the like.

[0186] Examples of a benzoxazolyl C1-6 alkyl group (which can be substituted on the benzoxazole ring by at least one oxo group as a substituent) include, for example, a benzoxazol-2-ylmethyl group, benzoxazol-4-ylmethyl group, benzoxazol-5-ylmethyl group, benzoxazol-6-ylmethyl group, benzoxazol-7-ylmethyl group, 2- (benzoxazol-4-yl) ethyl group, 1- (benzoxazol-5-yl) ethyl group, group 3- (benzoxazole -6yl) propyl, group 4- (benzoxazol-7-yl) butyl, group 5- (benzoxazol-2-yl) pentyl, group 6 (benzoxazol-4-yl) hexyl, group 2-methyl-3- (benzoxazol- 5-yl) propyl, 1,1-dimethyl-2 (benzoxazol-2-yl) ethyl group, (2,3-dihydro-2-oxo-benzoxazol-3-yl) methyl group, group (2,3 Petition 870190039560, of 26/04/2019, page 112/876

104/854 dihydro-2-oxo-benzoxazol-4-yl) methyl, group (2,3-dihydro-2-oxo-benzoxazol-5-yl) methyl, group (2,3-dihydro-2-oxo-benzoxazole -6-yl) methyl, (2,3-dihydro-2-oxo-benzoxazol-7yl) methyl, group 2- (benzoxazol-6-yl) ethyl, group 2- (benzoxazol-7-yl) ethyl, group 2- (2,3-dihydro-2-oxo-benzoxazol-3-yl) ethyl, group 2- (2,3-dihydro-2-oxo-benzoxazol-4-yl) ethyl, group 2- (2,3-dihydro -2-oxo-benzoxazol-5-yl) ethyl, group 2- (2,3-dihydro-2-oxo-benzoxazol6-yl) ethyl, group 2- (2,3-dihydro-2-oxo-benzoxazol-7 -yl) ethyl, group 3- (benzoxazol-2yl) propyl, 3- (benzoxazol-4-yl) propyl, group 3- (benzoxazol-5-yl) propyl, group 3 (benzoxazol-7-yl) propyl, group 3- (2,3-dihydro-2-oxo-benzoxazol-3-yl) propyl, group 3 (2,3-dihydro-2-oxo-benzoxazol-4-yl) propyl, group 3- (2,3- dihydro-2-oxo-benzoxazol-5yl) propyl, group 3- (2,3-dihydro-2-oxo-benzoxazol-6-yl) propyl, group 3- (2,3-dihydro-2-oxobenzoxazol-7- il) propyl, group 4- (benzoxazol-2-yl) butyl, group 4- (benzoxazol-4yl) butyl, group 4- (benzoxazol-5-yl) butyl, group 4- (benzoxazol-6-yl) bu tyl, group 4- (2,3-dihydro-2-oxo-benzoxazol-3-yl) butyl, group 4- (2,3-dihydro-2-oxo-benzoxazol-4-yl) butyl, group 4- (2, 3-dihydro-2-oxo-benzoxazol-5-yl) butyl, group 4- (2,3-dihydro-2-oxobenzoxazol-6-yl) butyl, group 4- (2,3-dihydro-2-oxo- benzoxazol-7-yl) butyl, group 5 (benzoxazol-4-yl) pentyl, group 5- (benzoxazol-5-yl) pentyl, 5- (benzoxazol-6-yl) pentyl, group 5- (benzoxazol-7- il) pentyl, group 5- (2,3-dihydro-2-oxo-benzoxazol-3-yl) pentyl, group 5- (2,3-dihydro-2-oxo-benzoxazol-4-yl) pentyl, group 5 - (2,3-dihydro-2-oxobenzoxazol-5-yl) pentyl, group 5- (2,3-dihydro-2-oxo-benzoxazol-6-yl) pentyl, group 5 (2,3-dihydro-2 -oxo-benzoxazol-7-yl) pentyl, group 6- (benzoxazol-2-yl) hexyl, group 6 (benzoxazol-5-yl) hexyl, group 6- (benzoxazol-6-yl) hexyl, group 6- ( benzoxazol-7yl) hexyl, group 6- (2,3-dihydro-2-oxo-benzoxazol-3-yl) hexyl, group 6- (2,3-dihydro-2-oxobenzoxazol-4-yl) hexyl, group 6 - (2,3-dihydro-2-oxo-benzoxazol-5-yl) hexyl, group 6- (2,3-dihydro-2-oxo-benzoxazol-6-yl) hexyl, group 6- (2,3-dihydro- 2-oxo-benzoxazole -7-yl) hexyl or the like.

[0187] A benzoxazolyl group includes, for example, a benzoxazol-2-yl group, benzoxazol-4-yl group, benzoxazol-5-yl group, benzoxazol-6-yl group, benzoxazol-7-yl group or the like.

[0188] Examples of an oxazolyl C1-6 alkyl group (which can be substituted on the oxazole ring by at least one group selected from a group consisting of a

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105/854 phenyl group and a C1-6 alkyl group as a substituent) include an oxazolyl C1-6 alkyl group (which can be substituted on the oxazole ring by 1 to 3 groups selected from a group consisting of a phenyl group and a C1-6 alkyl group as a substituent), for example, an oxazol-2-ylmethyl group, oxazol-4-ylmethyl group, oxazol-5-ylmethyl group, 2- (oxazol-2-yl) ethyl group, group 1- (oxazol-4-yl) ethyl, group 3- (oxazol5-yl) propyl, group 4- (oxazol-2-yl) butyl, group 5- (oxazol-4-yl) pentyl, group 6- (oxazol-5il ) hexyl, 2-methyl-3- (oxazol-2-yl) propyl group, 1,1-dimethyl-2- (oxazol-5-yl) ethyl group, methyl group (4-methyloxazol-2-yl), group (5-methyloxazol-2-yl) methyl, group (4-ethyloxazol2-yl) methyl, group (5-ethyloxazol-2-yl) methyl, group (4-n-propyloxazol-2-yl) methyl, group (5n -propyloxazol-2-yl) methyl, group (4-n-butyloxazol-2-yl) methyl, group (5-n-butyloxazol-2yl) methyl, group (4-n-pentyloxazol-2-yl) methyl, group (5-n-pentyloxazol-2-yl) methyl, (4-n-hexyloxazol-2-yl) methyl group, (5-n-hexyloxazol-2-yl) methyl group, 2- (oxazol-4yl) ethyl group, 2- (oxazol-5-yl) ethyl group, 2- (4-methyloxazol-2-yl) ethyl group, group 2- (5-methyloxazol-2-yl) ethyl, group 2- (4-ethyloxazol-2-yl) ethyl, group 2- (5-ethyloxazol-2-yl) ethyl, group 2- (4-n-propyloxazol- 2-yl) ethyl, group 2- (5-n-propyloxazol-2-yl) ethyl, group 2- (4-n-butyloxazol-2-yl) ethyl, group 2- (5-n-butyloxazol-2-yl) ethyl, group 2- (4-n-pentyloxazol-2yl) ethyl, group 2- (5-n-pentyloxazol-2-yl) ethyl, group 2- (4-n-hexyloxazol-2-yl) ethyl, group 2 (5-n-hexyloxazol-2-yl) ethyl, group 3- (oxazol-2-yl) propyl, group 3- (oxazol-4-yl) propyl, group 3- (4-methyloxazol-2-yl) propyl , group 3- (5-methyloxazol-2-yl) propyl, group 3- (4-ethyloxazol-2-yl) propyl, group 3- (5-ethyloxazol-2-yl) propyl, group 3- (4-n-propyloxazole -2yl) propyl, group 3- (5-n-propyloxazol-2-yl) propyl, group 3- (4-n-butyloxazol-2-yl) propyl, group 3- (5-n-butyloxazol-2-yl ) propyl, group 3- (4-n-pentyloxazol-2-yl) propyl, group 3- (5n-pentyloxazol-2-yl) propyl, group 3- (4-n-hexyloxazol-2-yl) pro pila, group 3- (5-nhexyloxazol-2-yl) propyl, group 4- (oxazol-4-yl) butyl, group 4- (oxazol-5-yl) butyl, group 4 (4-methyloxazol-2-yl ) butyl, group 4- (5-methyloxazol-2-yl) butyl, group 4- (4-ethyloxazol-2yl) butyl, group 4- (5-ethyloxazol-2-yl) butyl, group 4- (4-n -propyloxazol-2-yl) butyl, group 4 (5-n-propyloxazol-2-yl) butyl, group 4- (4-n-butyloxazol-2-yl) butyl, group 4- (5-n-butyloxazol-2- yl) butyl, 4- (4-n-pentyloxazol-2-yl) butyl group, 4- (5-n-pentyloxazol2-yl) butyl group, 4- (4-n-hexyloxazol-2-yl) butyl group, group 4- (5-n-hexyloxazol-2-yl) butyl, group 5- (oxazol-2-yl) pentyl, group 5- (oxazol-5-yl) pentyl, group 6- (oxazol-2-yl) hexyl,

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106/854 group 6- (oxazol-4-yl) hexyl, group (5-phenyloxazol-2-yl) methyl, group (2-phenyloxazol-4yl) methyl, group (2-phenyloxazol-5-yl) methyl, group 2- (5-phenyloxazol-2-yl) ethyl, group 2- (2-phenyloxazol-4-yl) ethyl, group 2- (2-phenyloxazol-5-yl) ethyl, group 3- (5-phenyloxazol-2yl) propyl , group 3- (2-phenyloxazol-4-yl) propyl, group 3- (2-phenyloxazol-5-yl) propyl, group

4- (5-phenyloxazol-2-yl) butyl, group 4- (2-phenyloxazol-4-yl) butyl, group 4- (2-phenyloxazol-5yl) butyl, group 5- (5-phenyloxazol-2-yl ) pentyl, group 5- (2-phenyloxazol-4-yl) pentyl, group 5 (2-phenyloxazol-5-yl) pentyl, group (2-phenyl-4-methyloxazol-5-yl) methyl, group (2, 4dimethyloxazol-5-yl) methyl, (2,5-diphenyloxazol-4-yl) methyl group or the like.

[0189] Examples of a tetrazolyl group (which can be substituted on the tetrazole ring by a phenyl group which can have C1-6 alkyl group (s) or halogen atom (s) as a substituent) include a tetrazolyl group (which can be substituted on the tetrazole ring by a phenyl group which may have 1 to 3 C1-6 alkyl groups or halogen atoms as the substituent (s)), for example, a 5 (IH) -tetrazolyl group, 1-methyl-5- group (1 H) -tetrazolyl, group 1-ethyl-5- (1 H) -tetrazolyl, group 1-n-propyl-5- (1 H) -tetrazolyl, group 1-isopropyl-5- (1 H) -tetrazolyl , group 1-n-butyl-5 (IH) -tetrazolyl, group 1- (2-methylpropyl) -5- (1 H) -tetrazolyl, group 1-n-pentyl-5- (1 H) tetrazolyl, group 1 -n-hexyl-5- (1 H) -tetrazolyl, group 1-phenyl-5- (1 H) -tetrazolyl, group 1 (4-chlorophenyl) -5- (1 H) -tetrazolyl, group 1- (4 -fluorophenyl) -5- (1 H) -tetrazolyl, group 1- (4bromophenyl) -5- (1 H) -tetrazolyl, group 1- (3,4-difluorophenyl) -5- (1 H) -tetrazolyl, group 1 (3,4-dichlorophenyl) -5- (1 H) -tetrazolyl, group 1- (3,4 , 5-trichlorophenyl) -5- (1 H) -tetrazolyl or the like.

[0190] A C1-8 alkyl group is a straight or branched alkyl group containing from 1 to 8 carbon atoms, examples of which include a methyl group, ethyl group, n-propyl group, isopropyl group, n group -butyl, isobutyl group, ter-butyl group, sec- [gap] group, n-pentyl group, neopentyl group, n-hexyl group, isohexyl group, 3-methylpentyl group, n-heptyla, 6-methylpile group, noctila group , 3,5-dimethylexyl group or the like.

[0191] Examples of a C1-6 alkyl group substituted by halogen atom (s) include a C1-6 alkyl group substituted by 1 to 7 halogens, for example, a fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, group

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107/854 dichloromethyl, trichloromethyl group, bromomethyl group, dibromomethyl group, dichlorofluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 2-chloroethyl group, 3,3,3-trifluoropropyl group, heptafluoropropyl group, heptaflu group 3-chloropropyl, group 2-chloropropyl, group 3-bromopropyl, group 4,4,4trifluorobutyl, group 4,4,4,3,3-pentafluorobutyl, group 4-chlorobutyl, group 4bromobutyl, group 2-chlorobutyl, group 5, 5,5-trifluoropentyl, 5-chloropentyl group, 6,6,6-trifluoroexyl group, 6-chlorohexyl group or the like.

[0192] A C1-6 alkoxycarbonyl group - C1-6 alkyl is a C1-6 alkyl group defined above replaced by the C1-6 alkoxycarbonyl group defined above, examples of which include a methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, group isopropoxycarbonylmethyl, n-butoxycarbonylmethyl group, ter-butoxycarbonylmethyl group, pentoxycarbonylmethyl group, nhexyloxycarbonylmethyl group, 2- (methoxycarbonyl) ethyl group, 2- (ethoxycarbonyl) ethyl group, 2- (1-propoxycarbonyl) ethyl group, 2- (isopropylcarbonyl) group ethyl, group 2- (n-butoxycarbonyl) ethyl, group 2- (ter-butoxycarbonyl) ethyl, group 2- (2-pentoxicarbonyl) ethyl, group 2- (n-hexyloxycarbonyl) ethyl, group 3- (methoxycarbonyl) propyl, group 3 (ethoxycarbonyl) propyl, group 3- (1-propoxycarbonyl) propyl, group 3 (isopropoxycarbonyl) propyl, group 3- (n-butoxycarbonyl) propyl, group 3- (terbutoxycarbonyl) propyl, group 3- (3-pentoxicarbonyl) propyl , group 3- (nhexyloxycarbonyl) propyl, group 4- (methoxycarbon il) butyl, group 4- (ethoxycarbonyl) butyl, group 4- (1-propoxycarbonyl) butyl, group 4- (isopropoxycarbonyl) butyl, group 4- (nbutoxycarbonyl) butyl, group 4- (ter-butoxycarbonyl) butyl, group 5 (methoxycarbonyl) pentyl, group 5- (ethoxycarbonyl) pentyl, group 5 (propoxycarbonyl) pentyl, group 5- (isopropoxycarbonyl) pentyl, group 5- (nbutoxycarbonyl) pentyl, group

5- (ter-butoxycarbonyl) pentyl, group 6 (methoxycarbonyl) hexyl, group 6- (ethoxycarbonyl) hexyl, group 6- (propoxycarbonyl) hexyl, group 6- (isopropoxycarbonyl) hexyl, group 6- (n-butoxycarbonyl) hexyl, group 6- (terbutoxycarbonyl) hexyl or similar.

[0193] A C3-8 cycloalkyl group is a cyclic alkyl group with 3 members, 4 members, 5 members, 6 members, 7 members or 8 members containing 3 to 8

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108/854 carbon atoms, examples of which include a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, 3,4-dimethylcyclopentyl group, 3,3-dimethylcyclo- hexyl or similar.

[0194] A phenyl C1-6 alkyl group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group or a halogen group C1-6 alkoxy unsubstituted or substituted by halogen) is a phenyl C1-6 alkyl group unsubstituted or substituted on the phenyl ring by 1 to 5 groups, preferably 1 to 3 groups selected from a group consisting of an atom of halogen, a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen, examples of which include a benzyl group, 1-phenethyl group, 2-phenethyl group, group 3 -phenylpropyl, 2-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 4-phenylpentyl group, 6-phenylexyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 3-chlorobenzyl group chlorine benzyl, 2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group, 2-iodobenzyl group, 3-iodobenzyl group, 4-iodobenzyl group, 2,3-difluorobenzyl group, 3,4-difluorobenzyl group, 3,5difluorobenzyl group , 2,4-difluorobenzyl group, 2,6-difluorobenzyl group, 2,3dichlorobenzyl group, 3,4-dichlorobenzyl group, 3,5-dichlorobenzyl group, 2,4dichlorobenzyl group, 2,6-dichlorobenzyl group, 2-fluoro group -4-bromobenzyl, 4-chloro3-fluorobenzyl group, 2,3,4-trichlorobenzyl group, 3,4,5-trifluorobenzyl group, 2,4,6trichlorobenzyl group, 4-isopropyl benzyl group, 4-n-butyl benzyl group, group 4-methylbenzyl, 2-methylbenzyl group, 3-methylbenzyl group, 2,4-dimethylbenzyl group, 2,3dimethylbenzyl group, 2,6-dimethylbenzyl group, 3,5-dimethylbenzyl group, 2,5dimethylbenzyl group, group 2,4, 6-trimethylbenzyl, 3,5-ditrifluoromethylbenzyl group, group

2,3,4,5,6-pentafluorobenzyl, 4-isopropoxybenzyl group, 4-n-butoxybenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 3-methoxybenzyl group, 2,4-dimethoxybenzyl group, 2,3-dimethoxybenzyl group , 2,6-dimethoxybenzyl group, 3,5-dimethoxybenzyl group, 2,5-dimethoxybenzyl group, 2,4,6-trimethoxybenzyl group, 3,5ditrifluoromethoxybenzyl group, 2-isopropoxybenzyl group, 3-chloro-4-methoxybenzyl group,

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109/854 2-chloro-4-trifluoromethoxybenzyl group, 3-methyl-4-fluorobenzyl group, 4-bromo3-trifluoromethylbenzyl group, 2-trifluoromethylbenzyl group, 3-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group , group 4-pentafluoroethylbenzyl, group 2-trifluoromethoxybenzyl, group 3-trifluoromethoxybenzyl, group 4-trifluoromethoxybenzyl, group 2-

pentafluoroethoxybenzyl, group 3-pentafluoroethoxybenzyl, group 4- pentafluoroethoxybenzyl, group 2- (2-trifluoromethylphenyl) ethyl, group 2- (3- trifluoromethylphenyl) ethyl, group 2- (4-trifluoromethylphenyl) ethyl, group 2- (2- trifluoromethoxyphenyl) ethyl, group 3- (trifluoromethoxyphenyl) ethyl, group 2- (3- trifluoromethoxyphenyl) ethyl, group 2- (2-pentafluoroethoxyphenyl) ethyl, group 2- (3- pentafluoroethoxyphenyl) ethyl, group 2- (4-pentafluoroethoxyphenyl) ethyl, group 3- (2- trifluoromethylphenyl) propyl, group 3- (3-trifluoromethylphenyl) propyl, group 3- (4- trifluoromethylphenyl) propyl, group 3- (2-trifluoromethoxyphenyl) propyl, group 3- (3- trifluoromethoxyphenyl) propyl, group 3- (4-trifluoromethoxyphenyl) propyl, group 3- (3- pentafluoroethoxyphenyl) propyl, group 3- (4-pentafluoroethoxyphenyl) propyl, group 4- (3- pentafluoroethoxyphenyl) butyl, group 5- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethoxyphenyl) pentyl, group 6- (3- trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethylphenyl) hexyl, group 6- (4-

trifluoromethoxyphenyl) hexyl or the like.

[0195] A phenyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of halogen atom (s), a substituted or unsubstituted C1-6 alkyl group by atom (s) of halogen, C1-6 alkoxy group unsubstituted or substituted by halogen, C1-6 alkanoyl group, carboxyl group, C1-6 alkoxycarbonyl group, a C1-6 phenyl alkoxycarbonyl group, carbamoyl group, C1-6 alkylcarbamoyl group, aminosulfonyl group and group morpholino) includes, for example, a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3bromophenyl group, group 4-bromophenyl, 2-iodophenyl group, 3-iodophenyl group, 4iodophenyl group, 2,3-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2,4-difluorophenyl group, group 2,6- difluorophenyl, group 2,3-dichlorophenyl, group 3,4

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110/854 dichlorophenyl, group 3,5-dichlorophenyl, group 2,4-dichlorophenyl, group 2,6-dichlorophenyl, group 3,4,5-trifluorophenyl, group 3,4,5-trichlorophenyl, group 2,4,6 -trifluorophenyl, group

2,4,6-trichlorophenyl, group 2-fluoro-4-bromophenyl, group 4-chloro-3-fluorophenyl, group

2,3,4-trichlorophenyl, group 4-isopropylphenyl, group 4-n-butylphenyl, group 2,4dimethylphenyl, group 2,3-dimethylphenyl, group 2,6-dimethylphenyl, group 3,5-dimethylphenyl, group 2.5 -dimethylphenyl, 2,4,6-trimethylphenyl group, 3,5-ditrifluoromethylphenyl group, group

4-n-butoxyphenyl, 2,4-dimethoxyphenyl group, 2,3-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 3,5ditrifluoromethoxyphenyl group, 3-chloro-4 group -methoxyphenyl, 2-chloro-4trifluoromethoxyphenyl group, 3-methyl-4-fluorophenyl group, 4-bromo-3-trifluoromethylphenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-trifluoromethyl group -trifluoromethylphenyl, 4-trifluoromethylphenyl group, 2-pentafluoroethylphenyl group, 3-pentafluoroethylphenyl group, 4-pentafluoroethylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 2-ter-butyl-group-3-teryl-butyl-group terbutylphenyl, group 2-sec-butylphenyl, group 3-sec-butylphenyl, group 4-sec-butylphenyl, group 2-n-heptafluoropropylphenyl, group 3-n-heptafluoropropylphenyl, group 4-nheptafluoropropylphenyl, group 4-n-group 4-n-hexylphenyl, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group la, 3-fluoro-2-methoxyphenyl group, 2-fluoro-3-methoxyphenyl group, 2-chloro-4methoxyphenyl group, 2,3,4-trimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, group 2,4, 6trimethoxyphenyl, 2-trifluoromethoxyphenyl group, 3-trifluoromethoxyphenyl group, 4trifluoromethoxyphenyl group, 2-pentafluoroethoxyphenyl group, 3-pentafluoroethoxyphenyl group, 2-isopropoxyphenyl group, 4-pentafluoroethoxyphenyl group, isopropylphenyl group butoxyphenyl, group 3-ter-butoxyphenyl, group 4-terbutoxyphenyl, group 2-sec-butoxyphenyl, group 3-sec-butoxyphenyl, group 4-secbutoxyphenyl, group 2-n-heptafluoropropoxyphenyl, group 3-n-heptafluoropropoxyphenyl, group 4- n-heptafluoropropoxyphenyl, group 4-pentoxiphenyl, group 4-hexyloxyphenyl, group 2-formylphenyl, group 3-formylphenyl, group 4-formylphenyl, group 2-acetylphenyl, group 3-acetylphenyl, group 4-acetylphenyl, group 2-propionylphen, group 2-propionylphen 3propionylphenyl, 4-propionylphenyl group, 2-butyrylphenyl group, 3-butyryl group Phenyl group

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111/854

4-butyrylphenyl, 2-pentanoylphenyl group, 3-pentanoylphenyl group, 4-pentanoylphenyl group, 2-hexanoylphenyl group, 3-hexanoylphenyl group, 4-hexanoylphenyl group, 2-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 2-metoxy group ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl group, 4-ethoxycarbonylphenyl group, 2-propoxycarbonylphenyl group, 3-propoxycarbonylphenyl group, 4propoxycarbonylphenyl group, 2-butoxycarbonylphenyl group, 3-butoxycarbonylphenyl group, group

4-butoxycarbonylphenyl, group 2-ter-butoxycarbonylphenyl, group 3-terbutoxycarbonylphenyl, group 4-ter-butoxycarbonylphenyl, group 2-pentoxicarbonylphenyl, group 3-pentoxycarbonylphenyl, group 4-pentoxycarbonylphenyl, group 4-hexyl group -hexyloxycarbonylphenyl, group 2-benzyloxycarbonylphenyl, group 3-benzyloxycarbonylphenyl, group 4benzyloxycarbonylphenyl, group 2-carboxylphenyl, group 3-carboxylphenyl, group 4carboxylphenyl, group 2-aminosulfonylphenyl, group 3-group-3-group carbamoylphenyl, 4carbamoylphenyl group, 2-methylcarbamoylphenyl group, 3-methylcarbamoylphenyl group, 3-methylcarbamoylphenyl group, 3-methylcarbamoylphenyl group, 2-ethylcarbamoylphenyl group, 2-ethylcarbamoylphenyl group, group 2-ethylcarbamoylphenyl group, 3-group , group 3 diethylcarbamoylphenyl, group 4-diethylcarbam oilphenyl, group 4-morpholinophenyl, group 3morpholinophenyl, group 4-morpholinophenyl or similar.

[0196] A C1-6 alkyl carbamoyl group is a group in which one or two hydrogens in the carbamoyl group (-CONH2) are replaced by the C1-6 alkyl group defined above, examples of which include an N-methylcarbamoyl group,

N-n-propylcarbamoyl, N-ter-butylcarbamoyl, group N-methyl-NN, N-dimethylcarbamoyl, group N-ethylcarbamoyl, group

N-isopropylcarbamoyl, N-n-butylcarbamoyl group, N-n-pentylcarbamoyl group, N-n-hexylcarbamoyl group, ethylcarbamoyl, isopropylcarbamoyl group, butylcarbamoyl group, hexylcarbamoyl group, group group group group group group group

N-methyl-N-n-propylcarbamoyl, N-methyl-N-n-butylcarbamoyl, N-methyl-N-n-pentylcarbamoyl, N-ethyl-N-isopropylcarbamoyl, group group group group group

N-methyl-NN-methyl-N-terN-methyl-N-nN-ethyl-N-terPetition 870190039560, from 26/04/2019, p. 120/876

112/854 butylcarbamoyl, N-propyl-N-ter-butylcarbamoyl group, N-isopropyl-N-terbutylcarbamoyl group or the like.

[0197] A phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and a non-substituted C1-6 alkoxy group substituted or substituted by halogen) is a phenyl group unsubstituted or substituted by 1 to 5, preferably 1 to 3 substituents selected from a group consisting of halogen (s), an unsubstituted or substituted C1-6 alkyl group halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen as defined above, examples of which include a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2chlorophenyl group, 3-chlorophenyl group , group 4-chlorophenyl, group 2-bromophenyl, group 3bromophenyl, group 4-bromophenyl, group 2-iodophenyl, group 3-iodophenyl, group 4iodophenyl, group 2,3-difluorophenyl, group 3,4-difluorophenyl, group 3,5 -difluorophenyl a, 2,4-difluorophenyl group, 2,6-difluorophenyl group, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, group 3,4,5-trifluorophenyl, group 3,4,5-trichlorophenyl, group 2,4,6-trifluorophenyl, group

2.4.6- trichlorophenyl, group 2-fluoro-4-bromophenyl, group 4-chloro-3-fluorophenyl, group

2,3,4-trichlorophenyl, group 2,3,4-trifluorophenyl, group 2,3,4,5,6-pentafluorophenyl, group

2.4.6- trimethylphenyl, group 4-n-butylphenyl, group 2,4-dimethylphenyl, group 2,3dimethylphenyl, group 2,6-dimethylphenyl, group 3,5-dimethylphenyl, group 2,5-dimethylphenyl, group 3,5 -ditrifluoromethylphenyl, group 4-n-butoxyphenyl, group 2,4-dimethoxyphenyl, group

2,3-dimethoxyphenyl, 2,6-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2,5dimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, 3,5-ditrifluoromethoxyphenyl group, 3chloro-4-methoxyphenyl group, group 2 -chloro-4-trifluoromethoxyphenyl, 3-methyl-4-fluorophenyl group, 4-bromo-3-trifluoromethylphenyl group, 2-methylphenyl group, 3-methylphenyl group, 4methylphenyl group, 2-methyl-3-chlorophenyl group, group 3- methyl-4-chlorophenyl, 2-chloro-4methylphenyl group, 2-methyl-3-fluorophenyl group, 2-trifluoromethylphenyl group, 3trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-pentafluoroethylphenyl group, 3pentafluoro group, 3pentafluoro group -isopropylphenyl, group 3

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113/854 isopropylphenyl, group 4-isopropylphenyl, group 2-ter-butylphenyl, group 3-ter-butylphenyl, group 4-ter-butylphenyl, group 2-sec-butylphenyl, group 3-sec-butylphenyl, group 4-secbutilphenyl, group 2-n-heptafluoropropylphenyl, group 3-n-heptafluoropropylphenyl, group

4-n-heptafluoropropylphenyl, group 4-pentylphenyl, group 4-hexylphenyl, group 2-methoxyphenyl, group 3-methoxyphenyl, group 4-methoxyphenyl, group 3-chloro-2-methoxyphenyl, group 2-fluoro-3-methoxyphenyl, group 2- fluoro-4-methoxyphenyl, group 3,4-dimethoxyphenyl, group group 3-trifluoromethoxyphenyl group,

3-fluoro-2-trifluoromethoxyphenyl,

3-fluoro-4-trifluoromethoxyphenyl,

2-chloro-3-trifluoromethoxyphenyl, group group group 42-fluoro-33-chloro-23-chloro-4group group 2-pentafluoroethoxyphenyl group, 3-pentafluoroethoxyphenyl group, 2-trifluoromethoxyphenyl, trifluoromethoxyphenyl, trifluoromethoxyphenyl, trifluoromethoxy, trifluoromethoxy, trifluoromethoxy -pentafluoroethoxyphenyl, 3-chloro-2-pentafluoroethoxyphenyl group, 2-chloro-3pentafluoroethoxyphenyl group, 3-chloro-4-pentafluoroethoxyphenyl group, 2isopropoxyphenyl group, 3-isopropoxyphenyl group, 2-isopropoxyphenyl group, 2-secoxyphenyl group , butoxyphenyl, heptafluoropropoxyphenyl group, heptafluoropropoxyphenyl, 3-ter-butoxyphenyl group, 4-ter-butoxyphenyl group,

3-sec-butoxyphenyl, group 4-sec-butoxyphenyl, group 3-n-heptafluoropropoxyphenyl, group 4-n-pentoxiphenyl, group 4-n-hexyloxyphenyl group group

4-nou similar.

[0198] A C1-6 phenyl alkoxycarbonyl group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of halogen atom (s), a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) is a group containing a phenyl C1-6 alkoxy group which can be substituted by 1 to 5, preferably 1 to 3 groups selected from a group consisting of halogen ( s), a C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen defined above and a carbonyl group, examples of which include a benzyloxycarbonyl group, 2-phenylethoxycarbonyl group, group 3- phenylpropoxycarbonyl, group 2-phenylpropoxycarbonyl, group

4-phenylbutoxycarbonyl, 5-phenylpentoxicarbonyl group, 4-phenylpentoxicarbonyl group,

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114/854

6-phenylexyloxycarbonyl, group 2-fluorobenzyloxycarbonyl, group

4-fluorobenzyloxycarbonyl,

2- (3-fluorophenyl) ethoxycarbonyl,

2-chlorobenzyloxycarbonyl,

4-chlorobenzyloxycarbonyl, group 2-fluoro-44-chloro-3-fluorobenzyloxycarbonyl, group 2,3,43,4,5-trifluorobenzyloxycarbonyl, group 2,3,4,5,6 group fluorobenzyloxycarbonyl, fluorophenyl) ethoxycarbonyl, fluorophenyl) ethoxycarbonyl, chlorobenzyloxycarbonyl, bromobenzyloxycarbonyl, trichlorobenzyloxycarbonyl, group group group group group group group

3 group group group

2- (22- (43pentafluorobenzyloxycarbonyl, group

2,4,6-trichlorobenzyloxycarbonyl, group 4-isopropoxybenzyloxycarbonyl, methylbenzyloxycarbonyl group, methylbenzyloxycarbonyl, dimethylbenzyloxycarbonyl, dimethylbenzyloxycarbonyl, group group group group group

4-n-butylbenzyloxycarbonyl,

2-methylbenzyloxycarbonyl,

2.4- dimethylbenzyloxycarbonyl,

2,6-dimethylbenzyloxycarbonyl,

2.5- dimethylbenzyloxycarbonyl, group group group group group

432,33,52,4,6trimethylbenzyloxycarbonyl, 3,5-ditrifluoromethylbenzyloxycarbonyl group, 4isopropoxybenzyloxycarbonyl group, 4-n-butoxybenzyloxycarbonyl group, 4methoxybenzyloxycarbonyl group, 2-methoxybenzyloxycarbonyl group, 2-methoxy group , 6-dimethoxybenzyloxycarbonyl, group3,5dimethoxybenzyloxycarbonyl, group 2,5-dimethoxybenzyloxycarbonyl, group 2,4,6trimethoxybenzyloxycarbonyl, group 3,5-ditrifluoromethoxybenzyloxycarbonyl, group 2 isopropoxybenzyloxycarbonyl, group 3-chloro-4-group-2-chloro-4-metoxib

4-trifluoromethoxybenzyloxycarbonyl, group 3-methyl-4-fluorobenzyloxycarbonyl, group 4-bromo-3-trifluoromethylbenzyloxycarbonyl, group 2- (2-chlorophenyl) ethyloxycarbonyl, group 2- (3-chlorophenyl) ethoxycarbonyl, group 2- (4-chlorophenyl) etoxicarbonila, 2trifluorometilbenziloxicarbonila group, 3-trifluorometilbenziloxicarbonila group, 4trifluorometilbenziloxicarbonila, 2-trifluorometoxibenziloxicarbonila group, 3trifluorometoxibenziloxicarbonila, 4-trifluorometoxibenziloxicarbonila group, 2- (2-trifluoromethylphenyl) etoxicarbonila group, 2- (3-trifluoromethylphenyl) etoxicarbonila group, 2- (4 -trifluoromethylphenyl) ethoxycarbonyl, group 2- (2-trifluoromethoxyphenyl) ethoxycarbonyl, group 2- (3-trifluoromethoxyphenyl) ethoxycarbonyl, group 2- (4Petition 870190039560, from 04/26/2019, page 123/876

115/854 trifluoromethoxyphenyl) ethoxycarbonyl, group 3- (2-trifluoromethylphenyl) propoxycarbonyl, group 3- (3-trifluoromethylphenyl) propoxycarbonyl, group 3- (4tnfluoromethylphenyl) propoxycarbonyl, group 3- (2-trifluoromethyl) propylcarbonyl (group 3) -trifluoromethoxyphenyl) propoxycarbonyl, group 3- (4trifluoromethoxyphenyl) propoxycarbonyl, group 4- (3-trifluoromethylphenyl) butoxycarbonyl, group 5- (4-trifluoromethylphenyl) pentoxycarbonyl, group 4- (4trifluoromethylcarbonyl-phenyl-pyridyl) phenyl-pentoxyl) , group 6- (3-trifluoromethylphenyl) hexyloxycarbonyl, group 6- (4trifluoromethylphenyl) hexyloxycarbonyl, group 6- (4-trifluoromethoxyphenyl) hexyloxycarbonyl or the like.

[0199] A phenyl C3-6 alkenyloxycarbonyl group (which can be substituted on the phenyl ring by at least one unsubstituted or substituted halogen C1-6 alkyl group) is a group containing an unsubstituted or substituted 1 to 3 phenyl group groups selected from a group consisting of C1-6 alkyl groups substituted or unsubstituted by halogen (s), an alkenyloxy group having 1 to 3 double bonds comprises from 3 to 6 carbons and a carbonyl group. These groups can be a trans form and a cis form, and both forms are of course included. Examples include a 3-phenyl-2-propenyloxycarbonyl group (common name: cinnamyloxycarbonyl group), 4-phenyl-2-butenyloxycarbonyl group, 4-phenyl3-butenyloxycarbonyl group, 5-phenyl-2-pentenyloxycarbonyl group, 5-phenyl- 4pentenyloxycarbonyl, group 5-phenyl-3-pentenyloxycarbonyl, group 6-phenyl-5hexenyloxycarbonyl, group 6-phenyl-4-hexenyloxycarbonyl, group 6-phenyl-3hexenyloxycarbonyl, group 6-phenyl-3-hexenyloxycarbonyl, group 4-phenyl-1-group 3butadienyloxycarbonyl, group 6-phenyl-1,3,5-hexatrienyloxycarbonyl, group 3- (2-methylphenyl) -2-propenyloxycarbonyl, group 3- (3-methylphenyl) -2-propenyloxycarbonyl, group 3- (4-methylphenyl) -2- propenyloxycarbonyl, group 3- (2-trifluoromethylphenyl) -2 propenyloxycarbonyl, group 3- (3-trifluoromethylphenyl) -2-propenyloxycarbonyl, group 3- (4trifluoromethylphenyl) -2-propenyloxycarbonyl, group 4- (2-trifluoromethylphenylcarbonyl), group 4- 4- (3-trifluoromethylphenyl) -3-butenyloxycarbonyl, group 4- (4trifluoromethylphenyl) -3-butenyloxycarbonyl, group 3- (3, 5-ditrifluoromethylphenyl) -2

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116/854 propenyloxycarbonyl, group 3- [2,4,6-tn (trifluoromethyl) phenyl] -2-propenyloxycarbonyl, group 3- (2,4-dimethylphenyl) -2-propenyloxycarbonyl or the like.

[0200] An amino group substituted by phenyl C1-6 alkylidene (which can be substituted by at least one unsubstituted or substituted C1-6 alkyl group as a substituent) is an amino group substituted by C1-6 alkylidene substituted by one phenyl group that can be substituted by 1 to 3 unsubstituted or substituted halogen C1-6 alkyl groups, examples of which include an amino benzylidene group, 2-phenylethylidene amino group, 3-phenylpropylidene amino group, 4-phenylbutyl amino group, 5-phenylpentylidene amino group,

6-phenylexylidene group amino, group 2-methylbenzylidene amino, group 2- thfluoromethylbenzylidene amino, group 3-methylbenzylidene amino, group 3- thfluoromethylbenzylidene amino, group 4-methylbenzylidene amino, group 4- thfluoromethylbenzylidene amino, 3,4-dimethylbenzylidene group amino, group 3,4,5-

amino thmethylbenzylidene, 3,5-dithfluoromethylbenzylidene amino group or the like. [0201] A phenoxy group (which can be substituted on the phenyl ring with at least one unsubstituted or substituted halogen C1-6 alkyl group) is an unsubstituted or substituted phenoxy group with 1 to 3 substituted or substituted C1-6 alkyl groups not substituted by halogen (s) as defined above, examples of which include a phenoxy group, 2-methylphenoxy group, 3-methylphenoxy group, 4-methylphenoxy group, 2-ethylphenoxy group, 3-ethylphenoxy group, 4-ethylphenoxy group , 4-n-propylphenoxy group, group

4-ter-butylphenoxy, 4-n-butylphenoxy group, 2-trifluoromethylphenoxy group, 3thfluoromethylphenoxy group, 4-trifluoromethylphenoxy group, 2-pentafluoroethylphenoxy group, 3pentafluoroethylphenoxy group, 2,3-group, 2,3-group 4-n-pentylphenoxy group, 4-n-hexyl-phenoxy group, 3,5-ditrifluoromethyl-phenoxy group or the like.

[0202] A phenylamino group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen-substituted C1-6 alkyl group) is an unsubstituted phenylamino group (another name: anilino group) or a phenylamino group substituted by de 1 to 3 C1-6 alkyl groups substituted or unsubstituted by halogen (s) defined above, examples of which include a phenylamino group, 2-methylphenylamino group, 3-methylphenylamino group, 4-methylphenylamino group,

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117/854 group 2-ethylphenylamino, group 3-ethylphenylamino, group 4-ethylphenylamino, group 4propylphenylamino, group 4-ter-butylphenylamino, group 4-butylphenylamino, group 2trifluoromethylphenylamino, group 3-trifluoramethylphenylphenylphenylphenylphenylphenylphenylphenylamino 3pentafluoroethylphenylamino, 2,3-dimethylphenylamino group, 3,4,5-trimethylphenylamino group, 4-n-pentylphenylamino group, 4-n-hexylphenylamino group, 3,5ditrifluoromethylphenylamino group or similar.

[0203] An indolinyl group that can be replaced by at least one halogen atom is an unsubstituted or substituted indolinyl group with 1 to 3 fluorine, chlorine, bromine or iodine at positions 2, 3, 4, 5, 6 or 7, examples of which include a 1-indolinyl ring, 2-fluoro-1-indolinyl group, 3-bromo-1-indolinyl group, 4,5-dichloro-1-indolinyl group, 4-fluoro-1 group -indolinyl, group 4,5,6-trifluoro-1 indolinyl, group 5-fluoro-1-indolinyl, group 6-fluoro-1-indolinyl, group 7-fluoro-1indolinyl, group 4-chloro-1-indolinyl, group 5-chloro-1-indolinyl, 6-chloro-1indolinyl group, 7-chloro-1-indolinyl group, 4-bromo-1-indolinyl group, 5-bromo-1indolinyl group, 6-bromo-1-indolinyl group, group 7-bromo-1-indolinyl, group 4-iodo-1indolinyl, group 5-iodo-1-indolinyl, group 6-iodo-1-indolinyl, group 7-iodo-1-indolinyl or the like.

[0204] An isoindolinyl group that can be replaced by at least one halogen atom is the unsubstituted or substituted indolinyl group with 1 to 3 fluorine, chlorine, bromine or iodine at positions 1, 3, 4, 5, 6 or 7, examples of which include a 2-isoindolinyl group, 1-fluoro-2-isoindolinyl group, 3bromo-2-isoindolinyl group, 4,5-dichloro-2-isoindolinyl group, 4,5,6-trifluoro group -2isoindolinyl, 4-fluoro-2-isoindolinyl group, 5-fluoro-2-isoindolinyl group, 6fluoro-2-isoindolinyl group, 7-fluoro-2-isoindolinyl group, 4-chloro-2-isoindolinyl group

5-chloro-2-isoindolinyl, 6-chloro-2-isoindolinyl group, 7-chloro-2-isoindolinyl group, 4-bromo-2-isoindolinyl group, 5-bromo-2-isoindolinyl group, 6-bromo-2isoindolinyl group , 7-bromo-2-isoindolinyl group, 4-iodo-2-isoindolinyl group, 5-iodo2-isoindolinyl group, 6-iodo-2-isoindolinyl group, 7-iodo-2-isoindolinyl group or the like.

[0205] A 1,2,3,4-tetrahydroquinolyl group that can be replaced by

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118/854 minus one halogen atom is a 1,2,3,4-tetrahydroquinolyl group unsubstituted or substituted by 1 to 3 fluorine, chlorine, bromine or iodine atoms in position 2, 3, 4, 5, 6, 7 or 8, examples of which include a 1,2,3,4-tetrahydro-1 quinolyl group, 5-fluoro-1,2,3,4-tetrahydro-1-quinolyl group, 2-bromo-1 group , 2,3,4-tetrahydro-

1-quinolyl, 3-iodo-1,2,3,4-tetrahydro-1-quinolyl, 4-chloro-1,2,3,4-tetrahydro-1quinolyl group, 3,4-dichloro-1,2 group, 3,4-tetrahydro-1-quinolyl, group 4,5,6-trichloro-1,2,3,4tetrahydro-1-quinolyl, group 6-fluoro-1,2,3,4-tetrahydro-1-quinolyl, group 7-fluoro-

1,2,3,4-tetrahydro-1-quinolyl, group 8-fluoro-1,2,3,4-tetrahydro-1-quinolyl, group 5-chloro-

1,2,3,4-tetrahydro-1-quinolyl, group 6-chloro-1,2,3,4-tetrahydro-1-quinolyl, group 7-chloro-

1.2.3.4- tetrahydro-1-quinolyl, 8-chloro-1,2,3,4-tetrahydro-1-quinolyl group, 5bromo-1,2,3,4-tetrahydro-1-quinolyl group, 6-bromo group -1,2,3,4-tetrahydro-1-quinolyl, group

7-bromo-1,2,3,4-tetrahydro-1-quinolyl, group 8-bromo-1,2,3,4-tetrahydro-1-quinolyl, group 5-iodo-1,2,3,4- tetrahydro-1-quinolyl, group 6-iodo-1,2,3,4-tetrahydro-1-quinolyl, group 7-iodo-1,2,3,4-tetrahydro-1-quinolyl, group 8-iodo-1 , 2,3,4-tetrahydro-1-quinolyl or the like.

[0206] A 1,2,3,4-tetrahydroisoquinolyl group that can be substituted by at least one halogen atom is a 1,2,3,4-tetrahydroisoquinolyl group that is unsubstituted or substituted by 1 to 3 fluorine atoms, chlorine, bromine or iodine at position 1, 3, 4, 5, 6, 7 or 8, examples of which include a 1,2,3,4-tetrahydro-2isoquinolyl group, 1-bromo-1,2 group, 3,4-tetrahydro-2-isoquinolyl, group 3-iodo-1,2,3,4tetrahydro-2-isoquinolyl, group 4-chloro-1,2,3,4-tetrahydro-2-isoquinolyl, group 3,4dichloro -1,2,3,4-tetrahydro-2-isoquinolyl, group 4,5,6-trichloro-1,2,3,4-tetrahydro-2isoquinolyl, group 5-fluoro-1,2,3,4-tetrahydro -2-isoquinolyl, group 6-fluoro-1,2,3,4tetrahydro-2-isoquinolyl, group 7-fluoro-1,2,3,4-tetrahydro-2-isoquinolyl, group 8-fluoro-

1.2.3.4- tetrahydro-2-isoquinolyl, 5-chloro-1,2,3,4-tetrahydro-2-isoquinolyl group, 6chloro-1,2,3,4-tetrahydro-2-isoquinolyl group, 7-chloro group -1,2,3,4-tetrahydro-2-isoquinolyl, 8-chloro-1,2,3,4-tetrahydro-2-isoquinolyl group, 5-bromo-1,2,3,4-tetrahydro-2isoquinolyl group , 6-bromo-1,2,3,4-tetrahydro-2-isoquinolyl group, 7-bromo-1,2,3,4tetrahydro-2-isoquinolyl group, 8-bromo-1,2,3,4- group tetrahydro-2-isoquinolyl, group 5-iodo-

1,2,3,4-tetrahydro-2-isoquinolyl, group 6-iodo-1,2,3,4-tetrahydro-2-isoquinolyl, group 7

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119/854 iodo-1,2,3,4-tetrahydro-2-isoquinolyl, group 8-iodo-1,2,3,4-tetrahydro-2-isoquinolyl, or the like.

[0207] A phenyl C1-6 alkyl group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of halogen atom (s), a C1-6 alkyl group unsubstituted or substituted by halogen or a C1-6 alkoxy group unsubstituted or substituted by halogen and a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of halogen atom (s), a C1-6 alkyl group not substituted or substituted by halogen and an unsubstituted or substituted C1-6 alkoxy group as a substituent), and also, the C1-6 alkyl moiety is replaced by a C1-6 alkoxy imino group) is a group containing a phenyl group unsubstituted or a phenyl group substituted by 1 to 5 groups, preferably 1 to 3 groups selected from a group consisting of a halogen atom, a substituted or unsubstituted C 1 -C 6 alkyl group, a group the C1-6 alkoxy unsubstituted or substituted by halogen and a phenoxy group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of a halogen atom, an unsubstituted C1-6 alkyl group or substituted by halogen or an unsubstituted C1-6 alkoxy group or substituted by halogen as a substituent) and containing an alkyl group having from 1 to 6 carbons, examples of which include a benzyl group, 1-phenethyl group, group 2- phenethyl, 3-phenylpropyl group, 2-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 4-phenylpentyl group, 6-phenylexyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4 fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 3-chlorobenzyl group , group 4-chlorobenzyl, group

2-bromobenzyl, group 3-bromobenzyl, group 4-bromobenzyl, group 2-iodobenzyl, group 3-iodobenzyl, group 4-iodobenzyl, group 2,3-difluorobenzyl, group 3,4difluorobenzyl, group 3,5-difluorobenzyl, group 2 , 4-difluorobenzyl, group 2,6difluorobenzyl, group 2,3-dichlorobenzyl, group 3,4-dichlorobenzyl, group 3,5dichlorobenzyl, group 2,4-dichlorobenzyl, group 2,6-dichlorobenzyl, group 2-fluoro-4bromobenzyl, group 4-chloro-3-fluorobenzyl, group 2,3,4-trichlorobenzyl, group 3,4,5trifluorobenzyl, group 2,3,4,5,6-pentafluorobenzyl, group 2,4,6-trichlorobenzyl, group

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120/854

4-isopropylbenzyl, group 4-n-butylbenzyl, group 4-methylbenzyl, group 2-methylbenzyl, group 3-methylbenzyl, group 2,4-dimethylbenzyl, group 2,3-dimethylbenzyl, group 2,6dimethylbenzyl, group 3,5- dimethylbenzyl, 2,5-dimethylbenzyl group, 2,4,6trimethylbenzyl group, 3,5-ditrifluoromethylbenzyl group, 4-isopropoxybenzyl group, 4-nbutoxybenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 3-methoxy group , 4-dimethoxybenzyl, 2,3-dimethoxybenzyl group, 2,6-dimethoxybenzyl group, 3,5-dimethoxybenzyl group, 2,5-dimethoxybenzyl group, 2,4,6-trimethoxybenzyl group, 3,5-ditrifluoromethoxybenzyl group, group 2-isopropoxybenzyl, group 3-chloro-4methoxybenzyl, group 2-chloro-4-trifluoromethoxybenzyl, group 3-methyl-4-fluorobenzyl, group 4-bromo-3-trifluoromethylbenzyl, group 2-trifluoromethylbenzyl, group 3-trifluoromethylbenzyl, group 3 , 2-pentafluoroethylbenzyl group, 3-pentafluoroethylbenzyl group, 4-pentafluoroethylbenzyl group, 2-trifluoromethane group xibenzyl, group 3-trifluoromethoxybenzyl, group 4-trifluoromethoxybenzyl, group 2-pentafluoroethoxybenzyl, group 3-pentafluoroethoxybenzyl, group 4-

pentafluoroethoxybenzyl, group 2- (2-trifluoromethylphenyl) ethyl, group 2- (3- trifluoromethylphenyl) ethyl, group 2- (4-trifluoromethylphenyl) ethyl, group 2- (2- trifluoromethoxyphenyl) ethyl, group 2- (3-trifluoromethoxyphenyl) ethyl, group 2- (3- trifluoromethoxyphenyl) ethyl, group 2- (2-pentafluoroethoxyphenyl) ethyl, group 2- (3- pentafluoroethoxyphenyl) ethyl, group 2- (4-pentafluoroethoxyphenyl) ethyl, group 3- (2- trifluoromethylphenyl) propyl, group 3- (3-trifluoromethylphenyl) propyl, group 3- (4- trifluoromethylphenyl) propyl, group 3- (2-trifluoromethoxyphenyl) propyl, group 3- (3- trifluoromethoxyphenyl) propyl, group 3- (4-trifluoromethoxyphenyl) propyl, group 3- (3- pentafluoroethoxyphenyl) propyl, group 3- (4-pentafluoroethoxyphenyl) propyl, group 4- (3- pentafluoroethoxyphenyl) butyl, group 5- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethoxyphenyl) pentyl, group 6- (3- trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethylphenyl) hexyl, group 6- (4- trifluoromethoxyphenyl) hexyl, group (4-pentafluoroethoxyphenyl) propyl, group 4- (3- pentafluoroethoxyphenyl) butyl, group 5- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethoxyphenyl) pentyl, group 6- (3- trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethylphenyl) hexyl, group 6- (4-

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121/854 trifluoromethoxyphenyl) hexyl, group 3-phenoxybenzyl, group 4-phenoxybenzyl, group 2- (4-phenoxyphenyl) ethyl, group 3- (4-phenoxyphenyl) propyl, group 2- (4-phenoxyphenyl) propyl, group 4 group group group group group group

4- (44- (34- (24- (4group

4- (4-trifluoromethylphenoxy) benzyl, group 4- (3-trifluoromethoxyphenoxy) benzyl, group

2- [4- (4-chlorophenoxy) phenyl] ethyl, group 2- [4- (43- [4- (4-chlorophenoxy) phenyl] propyl, group 3- [4- (4 (4-phenoxyphenyl) butyl, group 5- (4-phenoxyphenyl) pentyl, group 4- (4-phenoxyphenyl) pentyl, group 6- (4-phenoxyphenyl) hexyl, group 2-phenoxybenzyl, 2- (3-phenoxyphenyl) ethyl, group 3- (2phenoxyphenyl) propyl, 2- (2-phenoxyphenyl) propyl, group 4- (3-phenoxyphenyl) butyl, group 5- (2-phenoxyphenyl) pentyl, group 4- (3-phenoxyphenyl) pentyl, group 6- (3-phenoxyphenyl) hexyl, 4 - (2-chlorophenoxy) benzyl, group 4- (3-chlorophenoxy) benzyl, group chlorophenoxy) benzyl, group 4- (2-trifluoromethylphenoxy) benzyl, trifluoromethylphenoxy) benzyl, trifluoromethoxyphenoxy) benzyl, trifluoromethoxy) , trifluoromethylphenoxy) phenyl] propyl, group 3- [4- (4-trifluoromethoxyphenoxy) phenyl] propyl, group 2- [4- (4-chlorophenoxy) phenyl] propyl, group 4- [4- (4-chlorophenoxy) phenyl] butyl, group 4- [4- (4-trifluoromethylphenoxy) phenyl] butyl, group 4- [4- (4-trifluoromethoxyphenoxy) phenyl] butyl, group 5 [4- (4-chlorophenoxy ) phenyl] pentyl, group 4- [4- (4-chlorophenoxy) phenyl] pentyl, group 6- [4- (4-chlorophenoxy) phenyl] hexyl, group 6- [4- (4-trifluoromethylphenoxy) phenyl] hexyl, group 6 - [4- (4trifluoromethoxyphenoxy) phenyl] hexyl, group (2-fluoro-4-bromophenoxy) benzyl, group (4chloro-3-fluorophenoxy) benzyl, group (2,3,4-trichlorophenoxy) benzyl, group (3,4 , 5-

trifluorophenoxy) benzyl, group (2,4,6-trichlorophenoxy) benzyl, group (4- isopropylphenoxy) benzyl, (4-n-butylphenoxy) benzyl group, (4-methylphenoxy) benzyl group, (2-methylphenoxy) benzyl group, (3-methylphenoxy) benzyl group, group (2.4- dimethylphenoxy) benzyl, group (2,3-dimethylphenoxy) benzyl, group (2,6- dimethylphenoxy) benzyl, group (3,5-dimethylphenoxy) benzyl, group (2.5- dimethylphenoxy) benzyl, group (2,4,6-trimethylphenoxy) benzyl, group (3.5- ditrifluoromethylphenoxy) benzyl, (4-isopropoxyphenoxy) benzyl group, group (4-n-

butoxyphenoxy) benzyl, group (4-methoxyphenoxy) benzyl, group (2-methoxyphenoxy) benzyl, group (3-methoxyphenoxy) benzyl, group (2,4-dimethoxyphenoxy) benzyl, group (2,3dimethoxyphenoxy) benzyl, group (2, 6-dimethoxyphenoxy) benzyl, group (3,5dimethoxyphenoxy) benzyl, group (2,5-dimethoxyphenoxy) benzyl, group (2,4,6

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122/854 trimethoxyphenoxy) benzyl, group (3,5-ditrifluoromethoxyphenoxy) benzyl, group (2isopropoxyphenoxy) benzyl, group (3-chloro-4-methoxyphenoxy) benzyl, group (2-chloro-4trifluoromethoxyphenoxy) benzyl, group (3 -4-fluorophenoxy) benzyl, (4-bromo-3trifluoromethylphenoxy) benzyl group or the like.

[0208] A benzoyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group and a C1-6 alkoxy group unsubstituted or substituted by halogen) include the benzoyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of halogen atom (s), a C1 alkyl group -6 unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen), for example, benzoyl group, 2-fluorobenzoyl group,

3-fluorobenzoyl, group 4-fluorobenzoyl, group 2,3-difluorobenzoyl, group 2,3,4,5,6pentafluorobenzoyl, group 3,4-difluorobenzoyl, group 2-chlorobenzoyl, group 3chlorobenzoyl, group 4-chlorobenzoyl, group 2, 3-dichlorobenzoyl, group 3,4dichlorobenzoyl, group 2-bromobenzoyl, group 3-bromobenzoyl, group 4bromobenzoyl, group 2,3-dibromobenzoyl, group 3,4-dibromobenzoyl, group 2fluoro-4-bromobenzoyl, group 4-chloro-3- fluorobenzoyl, 2,3,4-trifluorobenzoyl group, 2,4,6-trichlorobenzoyl group, 4-isopropyl benzoyl group, 4-n-butyl benzoyl group, group

2.4- dimethylbenzoyl, 2,3-dimethylbenzoyl group, 2,6-dimethylbenzoyl group, 3,5dimethylbenzoyl group, 2,5-dimethylbenzoyl group, 2,4,6-trimethylbenzoyl group, 3,5ditrifluoromethyl benzoyl group, 4-n-butoxybenzyl group , 2,4-dimethoxybenzoyl group, group

2,3-dimethoxybenzoyl, 2,6-dimethoxybenzoyl group, 3,5-dimethoxybenzoyl group, group

2.5- dimethoxybenzoyl, 3,5-ditrifluoromethoxybenzoyl group, 3-chloro-4-methoxybenzoyl group, 2-chloro-4-tnfluoromethoxybenzoyl group, 3-methyl-4fluorobenzoyl group, 4-bromo-3-trifluoromethyl benzoyl group, 2-methoxy group 3-methylbenzoyl group, 4-methylbenzoyl group, 3,4-dimethylbenzoyl group, 2iodobenzoyl group, 3-iodobenzoyl group, 4-iodobenzoyl group, 2trifluoromethylbenzoyl group, 3-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 3-trifluoromethylbenzyl group 3,4-ditrifluoromethylbenzoyl group, group 2

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123/854 methoxybenzoyl, 3-methoxybenzoyl group, 4-methoxybenzoyl group, 2trifluoromethoxybenzoyl group, 3-trifluoromethoxybenzoyl group, 4trifluoromethoxybenzoyl group or the like.

[0209] Examples of a pyridyl group (which can be substituted on the pyridine ring by at least one halogen atom as a substituent) include a pyridyl group (which can be substituted on the pyridine ring by 1 to 3 halogen atoms as a substituent ), for example, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-chloropyridin-3-yl group, 2-chloropyridin-4-yl group, 2-chloropyridin-5-yl group, group

5-chloropyridin-2-yl, group 4-chloropyridin-2-yl, group 3-chloropyridin-2-yl, group 2fluoropyridin-3-yl, group 2-fluoropyridin-4-yl, group 2-fluoropyridin-5-yl , group5-fluoropyridin-2-yl, group 4-fluoropyridin-2-yl, group 3-fluoropyridin-2-yl, group2bromopyridin-3-yl, group 2-bromopyridin-4-yl, group 2-bromopyridin-5-yl , group5bromopyridin-2-yl, group 4-bromopyridin-2-yl, group 3-bromopyridin-2-yl, group2bromo-4-chloropyridin-4-yl, group 2,6-dichloropyridin-4-yl, group 2,4 , 6-trichloropyridin-3-yl or the like.

[0210] A C1-6 alkyl phenoxy group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of halogen atom (s), a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) is a group containing a phenoxy group unsubstituted or substituted by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a C1-6 alkyl group unsubstituted or substituted by halogen and an unsubstituted or substituted C1-6 alkoxy group defined above and a C1-6 alkyl group, examples of which include a phenoxymethyl group, 2-phenoxyethyl group, 3-phenoxypropyl group, group 4- phenoxybutyl, 5-phenoxypentyl group, 6-phenoxyxy group, 4fluorophenoxymethyl group, 2-fluoro-4-bromophenoxymethyl group, 4-chloro-3fluorophenoxymethyl group, 2,3,4-trichlorophenoxymethyl group, group 3,4,5-trichlorophenoxymethyl, group 2, 4,6-trichlorophenoxymethyl, 4-isopropylphenoxymethyl group, 4-nbutylphenoxymethyl group, 4-methylphenoxymethyl group, 2-methylphenoxymethyl group, 3methylphenoxymethyl group, 2,4-dimethylphenoxymethyl group, 2,3-dimethylphen group

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124/854

2,6-dimethylphenoxymethyl, 3,5-dimethylphenoxymethyl group, 2,5-dimethylphenoxymethyl group, 2,4,6-trimethylphenoxymethyl group, 3,5-ditrifluoromethylphenoxymethyl group, 2,3,4,5,6pentafluorophenoxymethyl group, group 4- isopropoxyphenoxymethyl, 4-n-butoxyphenoxymethyl group, 4-methoxyphenoxymethyl group, 2-methoxyphenoxymethyl group, 3-methoxyphenoxymethyl group, 2,4-dimethoxyphenoxymethyl group, 2,3-dimethoxyphenoxymethyl group, 2,6-dimethoxyphenoxymethyl group, 3,5-dimethoxyphenoxymethyl group, group 2,5-dimethoxyphenoxymethyl, group 2-chloro-4group 2,4,6-trimethoxyphenoxymethyl, group 3,5-ditrifluoromethoxyphenoxymethyl, group 2isopropoxyphenoxymethyl, group 3-chloro-4-methoxyphenoxymethyl, trifluoromethoxyphenoxymethyl, group 3-methoxymethyl , group 4-bromo-3trifluoromethylphenoxymethyl, group 2- (4-fluorophenoxy) ethyl, group 3- (4-fluorophenoxy) propyl, group 4- (4-fluorophenoxy) butyl, group 5- (4-fluorophenoxy) pentyl, group 6 - (4fluorophenoxy) hexyl, group 4-chlorophenoxymethyl, group 2- (4-chlorophenoxy) ethyl, group 3- (4-chlorophenoxy) propyl, group 4- (4-chlorophenoxy) butyl, group 5- (4-chlorophenoxy) pentyl, group

6- (4-chlorophenoxy) hexyl, 4-methylphenoxymethyl group, 2- (4-methylphenoxy) ethyl group, 3- (4-methylphenoxy) propyl group, 4- (4-methylphenoxy) butyl group, group 5- (4- methylphenoxy) pentyl,

group 6- (4-methylphenoxy) hexyl, group 4-trifluoromethylphenoxymethyl, group 2- (4- trifluoromethylphenoxy) ethyl, group 3- (4-trifluoromethylphenoxy) propyl, group 4- (4- trifluoromethylphenoxy) butyl, group 5- (4-trifluoromethylphenoxy) pentyl, group 6- (4- trifluoromethylphenoxy) hexyl, group 4-trifluoromethoxyphenoxymethyl, group 2- (4- trifluoromethoxyphenoxy) ethyl, group 3- (4-trifluoromethoxyphenoxy) propyl, group 4- (4- trifluoromethoxyphenoxy) butyl, group 5- (4-trifluoromethoxyphenoxy) pentyl, group 6- (4- trifluoromethoxyphenoxy) hexyl, group 2- (4-methoxyphenoxy) ethyl, group 3- (4-

methoxyphenoxy) propyl, group 4- (4-methoxyphenoxy) butyl, group 5- (4-methoxyphenoxy) pentyl, group 6- (4-methoxyphenoxy) hexyl or the like.

[0211] A benzoyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and a group C1-6 alkoxy unsubstituted or substituted by halogen) includes a benzoyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of an atom of halogen one

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125/854 C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen), for example, a benzoylmethyl group, 2-benzoylethyl group, 1-benzoylethyl group, 3-benzoylpropyl group , 4benzoylbutyl group, 5-benzoylpentyl group, 6-benzoylexyl group, 2-methyl-3benzoylpropyl group, 1,1-dimethyl-2-benzoylethyl group, 2-fluorobenzoylmethyl group, 3-fluorobenzoylmethyl group, 4-fluorobenzylmethyl group, 2-chlorobenzyl group 3chlorobenzoylmethyl group, 4-chlorobenzoylmethyl group, 2-bromobenzoylmethyl group, 3bromobenzoylmethyl group, 4-bromobenzoylmethyl group, 2-fluoro-4bromobenzoylmethyl group, 4-chloro-3-fluorobenzoylmethyl group, 2,3,4trichlorobenzoylmethyl group, group -trichlorobenzoylmethyl, 4-isopropylbenzoylmethyl group, 4-n-butylbenzoylmethyl group, 2,4-dimethylbenzoylmethyl group, 2,3 dimethylbenzoylmethyl group, 2,6-dimethylbenzoylmethyl group, 3,5-dimethylbenzoylmethyl group, 2,5-dimethylbenzoylme group tila, 2,4,6-trimethylbenzoylmethyl group, 3,5ditrifluoromethylbenzoylmethyl group, 2,3,4,5,6-pentafluorobenzoylmethyl group, 4-nbutoxybenzoylmethyl group, group

2,4-dimethoxybenzoylmethyl, group

2,3dimethoxybenzoylmethyl, 2,6-dimethoxybenzoylmethyl group, 3,5dimethoxybenzoylmethyl group, 2,5-dimethoxybenzoylmethyl group, 3,5ditrifluoromethoxybenzoylmethyl group, 3-chloro-4-methoxybenzylmethyl, trifluoromethylmethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl trifluoromethoxybenzoylmethyl, fluorobenzoyl) ethyl, group 2- (4-fluorobenzoyl) ethyl, group 2- (2-chlorobenzoyl) ethyl, group 3-methyl-4-fluorobenzoylmethyl group, group 4-bromo-3-

2- trifluoromethylbenzoylmethyl,

4-trifluoromethylbenzoylmethyl,

3- trifluoromethoxybenzoylmethyl,

2- (2-fluorobenzoyl) ethyl, group group group

3group group group group group

242- (32- (3-chlorobenzoyl) ethyl, group 2- (4-chlorobenzoyl) ethyl, group 2- (2-bromobenzoyl) ethyl, group 2- (3-bromobenzoyl) ethyl, group 2- (4-bromobenzoyl) ethyl, group 2- (2trifluoromethylbenzoyl) ethyl, group

2- (3-trifluoromethylbenzoyl) ethyl, group

2- (4trifluoromethylbenzoyl) ethyl, group 2- (2-trifluoromethoxybenzoyl) ethyl, group 2- (3-trifluoromethoxybenzoyl) ethyl, group 2- (4-trifluoromethoxybenzoyl) ethyl, group 3- (2-chlorobenzoyl) propyl, group 3- (3-chlorobenzoyl) ) propyl, group 3- (4-chlorobenzoyl) propyl,

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126/854 group 3- (2-trifluoromethylbenzoyl) propyl, group 3- (3-trifluoromethylbenzoyl) propyl, group 3- (4-trifluoromethylbenzoyl) propyl, group 3- (2-trifluoromethoxybenzoyl) propyl, group 3- (3trifluoromethoxybenzyl) propyl , group 3- (4-trifluoromethoxybenzoyl) propyl, group 4- (2-chlorobenzoyl) butyl, group 4- (3-chlorobenzoyl) butyl, group 4- (4-chlorobenzoyl) butyl, group 4- (2-trifluoromethylbenzoyl) butyl, group 4- (3-trifluoromethylbenzoyl) butyl, group 4 (4-trifluoromethylbenzoyl) butyl, group 4- (2-trifluoromethoxybenzoyl) butyl, group 4- (3-trifluoromethoxybenzoyl) butyl, group 4- (4-trifluoromethoxybenzoyl) butyl, group 5- ( 2chlorobenzoyl) pentyl, group 5- (3-chlorobenzoyl) pentyl, group 5- (4-chlorobenzoyl) pentyl, group 5- (2-trifluoromethylbenzoyl) pentyl, group 5- (3-trifluoromethylbenzoyl) pentyl, group

5- (4-trifluoromethylbenzoyl) pentyl, group 5- (2-trifluoromethoxybenzoyl) pentyl, group 5- (3-trifluoromethoxybenzoyl) pentyl, group 5- (4-trifluoromethoxybenzoyl) pentyl, group 6- (2chlorobenzoyl) hexyl, group 6- (3 -chlorobenzoyl) hexyl, group 6- (4-chlorobenzoyl) hexyl, group 6- (2-trifluoromethylbenzoyl) hexyl, group 6- (3-trifluoromethylbenzoyl) hexyl, group 6 (4-trifluoromethylbenzoyl) hexyl, group 6- (2- trifluoromethoxybenzoyl) hexyl, group 6- (3trifluoromethoxybenzoyl) hexyl, group 6- (4-trifluoromethoxybenzoyl) hexyl or the like.

[0212] A phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom; C1-6 alkyl group unsubstituted or substituted by halogen; C1-6 alkoxy group unsubstituted or substituted by halogen; C1-4 alkylenedioxy group; C1-6 alkoxycarbonyl group; cyano group; C2-6 alkenyl group; nitro group; phenyl group; an amino group that may have a group selected from a group consisting of a phenyl group , C1-6 alkyl group, carbamoyl group and C1-6 alkanoyl group as a substituent; C1-6 alkyl group substituted by a C1-6 alkanoyl group; hydroxyl group; C1-6 alkyl group substituted by a C1-6 alkoxycarbonyl group; phenyl C1-6 alkyl group; C1-8 alkanoyl group; C1-6 alkylthio group; 1,2,4-triazolyl group; isoxazolyl group; imidazolyl group; benzothiazolyl group; 2H-benzotriazolyl group; pyrolyl group; benzoxazolyl group; piperazinyl group (which can be replaced in the piperazine ring by at least one group selected from a group consisting of a C1-6 alkoxycarbonyl group and a C1-6 phenyl alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of one

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127/854 halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent); piperidyl group (which can be substituted on the piperidine ring by at least one amino group (which can be substituted on the amino group by at least one group selected from a group consisting of the C1-6 alkyl and phenyl group (which can be substituted on the phenyl ring for at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent); and carbamoyl group)) includes a phenoxy group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom; an unsubstituted C 1-6 alkyl group or substituted by halogen; C1-6 alkoxy group unsubstituted or substituted by halogen; C1-4 alkylenedioxy group; C1-6 alkoxycarbonyl group; cyano group; C2-6 alkenyl group; nitro group; phenyl group; an amino group in which it may have from 1 to 2 groups selected from a group consisting of phenyl group, C1-6 alkyl group, carbamoyl group and C1-6 alkanoyl group as a substituent; C1-6 alkyl group substituted by a C1-6 alkanoyl group; hydroxyl group; C1-6 alkyl group substituted by a C1-e alkoxycarbonyl group; phenyl C1-alkyl group; C 1-6 alkanoyl group; C 1-6 alkylthio group; 1,2,4-triazolyl group; isoxazolyl group; imidazolyl group; benzothiazolyl group; 2H-benzothazolyl group; pyrolyl group; benzoxazolyl group; piperazinyl group (which can be substituted on the piperazine ring by 1 to 3 groups selected from a group consisting of a C16 alkoxycarbonyl group and phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5, preferably from 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent); piperidyl group (which can be substituted on the piperidine ring by 1 to 3 groups selected from a group consisting of an amino group (which can be substituted on the amino group by 1 to 5, preferably from 1 to 3 groups selected from an group consisting of a C1-6 alkyl and phenyl group (which can be substituted on the phenyl ring

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128/854 by 1 to 5, preferably 1 to 3 groups in a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen ) as a substituent) and carbamoyl group), for example, a phenoxy group, 2-fluorophenoxy group, 3-fluorophenoxy group, 4-fluorophenoxy group, 2-chlorophenoxy group, 3-chlorophenoxy group, 4-chlorophenoxy group, group 2- bromophenoxy, 3-bromophenoxy group, 4-bromophenoxy group, 2-iodophenoxy group,

3-iodophenoxy group, 4-iodophenoxy group, group 2,3-difluorophenoxy, group 3.4- difluorophenoxy, group 3,5-difluorophenoxy, group 2,4-difluorophenoxy, group 2.6- difluorophenoxy, group 2,3-dichlorophenoxy, group 3,4-dichlorophenoxy, group 3.5- dichlorophenoxy, group 2,4-dichlorophenoxy, group 2,6-dichlorophenoxy, group 2,3,4- trifluorophenoxy, group 3,4,5-trifluorophenoxy, group 3,4,5-trichlorophenoxy, group 2.4.6-

trifluorophenoxy, 2,3,4,5,6-pentafluorophenoxy group, 2,4,6-trichlorophenoxy group, 2fluoro-4-chlorophenoxy group, 2-fluoro-4-bromophenoxy group, 3-fluoro-4-chlorophenoxy group, group 2-methylphenoxy, 3-methylphenoxy group, 4-methylphenoxy group, 2,6-dimethylphenoxy group, group

2,4,6-trimethylphenoxy, 2-methyl-3-chlorophenoxy group, 3-methyl-4-chlorophenoxy group, 2chloro-4-methylphenoxy group, 2-methyl-3-fluorophenoxy group, 2-trifluoromethylphenoxy group, 3trifluoromethylphenoxy group, 4-trifluoromethylphenoxy group, 3,5-di (trifluoromethyl) phenoxy, 3,4di (trifluoromethyl) phenoxy group, 2,4-di (trifluoromethyl) phenoxy group, 2-pentafluoroethylphenoxy group, 3-pentafluoroethylphenoxy group, 4-pentafluoro group , 2-isopropylphenoxy group, 3-isopropylphenoxy group, 4-isopropylphenoxy group, 2-ter-butylphenoxy group, 3-terbuthyloxy group, 4-ter-butylphenoxy group, 2-sec-butylphenoxy group, 3-sec-butylphenoxy group, group 4-sec-butylphenoxy, group 4-n-butylphenoxy, group 4-n-pentylphenoxy, group 4-nhexylphenoxy, group 2-n-heptafluoropropylphenoxy, group 3-n-heptafluoropropylphenoxy, group 4-n-heptafluoxyphenoxypropylphenoxypropyl , 4-hexylphenoxy group, 2-methoxyphenoxy group, 3-methoxy-phenoxy group, 4-methoxy-phenoxy group, 2-methoxy-3-chlorophenoxy group, group 2-fluoro-3-methoxyphenoxy, 2-fluoro-4-methoxyphenoxy group, 2fluoro-4-bromophenoxy group, 2,4-dimethylphenoxy group, 2,3-dimethylphenoxy group, 3,5-dimethylphenoxy group, 2,5-dimethylphenoxy group, 4-isopropoxyphenoxy group, 4-nbutoxyphenoxy group, 2,4-dimethoxyphenoxy group, 2,3-dimethoxyphenoxy group, 3,5-dimethoxyphenoxy group, 2,5-dimethoxyphenoxy group, 2,4,6-trimethoxyphenoxy group, 3,5 group

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129/854 ditrifluoromethoxyphenoxy, 2-isopropoxyphenoxy group, 3-chloro-4-methoxyphenoxy group, group

2-chloro-4-trifluoromethoxyphenoxy, 3-methyl-4-fluorophenoxy group, 4-bromo-3trifluoromethylphenoxy group, 2,6-dimethoxyphenoxy group, 2-trifluoromethoxyphenoxy group, 3trifluoromethoxyphenoxy group, 4-trifluoromethoxy group (trifluoromethoxy) phenoxy, 3,5-di (trifluoromethoxy) phenoxy group, 2,4-di (trifluoromethoxy) phenoxy group, 2pentafluoroethoxyphenoxy group, 3-pentafluoroethoxyphenoxy group, 4pentafluoroethoxyphenoxy group, 3-isopropoxyphenoxy group, 3-isopropoxyphenoxy group group 3-terbutoxyphenoxy, group 4-ter-butoxyphenoxy, group 2-sec-butoxyphenoxy, group 3-secbutoxyphenoxy, group 4-sec-butoxyphenoxy, group 4-n-hexyloxyphenoxy, group 2-nheptafluoropropoxyphenoxy, group 3-n-nop 4-nheptafluoropropoxyphenoxy group, 2,3-methylenedioxyphenoxy group, 3,4-methylenedioxyphenoxy group, 2,3-ethylenedioxyphenoxy group, 3,4-ethylenedioxyphenoxy group, 2-methoxycarbonylphenoxy group, 3-methoxycarbonylphenoxy group, 2-group xi, 3-ethoxycarbonylphenoxy group, 4-ethoxycarbonylphenoxy group, 4-propoxycarbonylphenoxy group, 4-butoxycarbonylphenoxy group, 4pentoxicarbonylphenoxy group, 4-hexyloxycarbonylphenoxy group, 2-cyanophenoxy group, 2,3-group 2,4,6-tricycophenoxy group, 2-vinylphenoxy group, 3-vinylphenoxy group, 4-vinylphenoxy group, 2-allyphenoxy group, 3allylphenoxy group, 4-allylphenoxy group, 2- (3-butenyl) phenoxy group, group 3- (3-butenyl) phenoxy, group

4- (3-butenyl) phenoxy, group 2- (4-pentenyl) phenoxy, group 3- (4-pentenyl) phenoxy, group 4- (4-pentenyl) phenoxy, group 2- (5-hexenyl) phenoxy, group 3- (5-hexenyl) phenoxy, group 4- (5hexenyl) phenoxy, group 2-nitrophenoxy, group 3-nitrophenoxy, group 4-nitrophenoxy, group 2,3-dinitrophenoxy, group 2,4-dinitrophenoxy, group 2,4,6-trinitrophenoxy , 2-biphenyloyloxy group, 3-biphenylyloxy group, 4-biphenylyloxy group, 2-dimethylaminophenoxy group, 3dimethylaminophenoxy group, 4-dimethylaminophenoxy group, 2-diethylaminophenoxy group, 3dethylaminophenoxy group, 3-diethylaminoxy group, 4-diethylaminoxy group propyl) aminophenoxy, group

3- di- (n-propyl) aminophenoxy, group 4-di- (n-propyl) aminophenoxy, group 2-diphenylaminophenoxy, group 3-diphenylaminophenoxy, group 4-diphenylaminophenoxy, group 2acetylaminophenoxy, group 3-acetylaminophenoxy, group 4-acetyloxy , 2propionylaminophenoxy group, 3-propionylaminophenoxy group, 4-propionylaminophenoxy group,

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130/854 group 2-butyrylaminophenoxy, group 3-butyrylaminophenoxy, group 4-butyrylaminophenoxy, group 4-pentanoylaminophenoxy, group 4-hexanoylaminophenoxy, group 3- (N-methyl-N-phenylamino) phenoxy, group 2- (N-acetyl-N- methylamino) phenoxy, group 2carbamoylaminophenoxy, group 3-carbamoylaminophenoxy, group 4-carbamoylaminophenoxy, group 4- (N-acetyl-N-phenylamino) phenoxy, group 4-acetylmethylphenoxy, group 4propionylmethylphenoxy, group 4-n-butyrylmethyl, group 4-n-butyrylmethyl 2-acetylethyl) phenoxy, group 4 (3-acetylpropyl) phenoxy, group 4- (4-acetylbutyl) phenoxy, group 4- (5-acetylpentyl) phenoxy, group

4- (6-acetylexyl) phenoxy, 2-hydroxyphenoxy group, 3-hydroxyphenoxy group, 4-hydroxyphenoxy group, 2,4-dihydroxyphenoxy group, 2,4,6-trihydroxyphenoxy group, 2-hydroxy-3 chlorophenoxy group, 2-fluoro-group 3-hydroxyphenoxy, group 2-fluoro-4-hydroxyphenoxy, group 4-

methoxycarbonylmethylphenoxy, group 4-ethoxycarbonylmethylphenoxy, group 4-n- propoxycarbonylmethylphenoxy, group 4- (2-ethoxycarbonylethyl) phenoxy, group 4- (3- ethoxycarbonylpropyl) phenoxy, group 4- (4-ethoxycarbonylbutyl) phenoxy, group 4- (5-

ethoxycarbonylpentyl) phenoxy, group 4- (6-ethoxycarbonylexyl) phenoxy, group 2-benzylphenoxy, group 3-benzylphenoxy, group 4-benzylphenoxy, group 2- (2-phenylethyl) phenoxy, group 3- (2phenylethyl) phenoxy, group 4- (2-phenylethyl) phenoxy, group 2- (3-phenylpropyl) phenoxy, group 3- (3-phenylpropyl) phenoxy, group 4- (3-phenylpropyl) phenoxy, group 2- (4-phenylbutyl) phenoxy, group 3- (4-phenylbutyl) ) phenoxy, group 4- (4-phenylbutyl) phenoxy, group 2- (5-phenylpentyl) phenoxy, group 3- (5-phenylpentyl) phenoxy, group 4- (5-phenylpentyl) phenoxy, group 2- (6-phenylexyl) phenoxy , group 3- (6phenylexyl) phenoxy, group 4- (6-phenylexyl) phenoxy, group 2-acetylphenoxy, group 3-acetylphenoxy, group 4-acetylphenoxy, group 4-n-propionylphenoxy, group 4-n-butyrylphenoxy, group 4 -npentanoylphenoxy, 4-n-hexanoylphenoxy group, 2-methylthiophenoxy group, 3methylthiophenoxy group, 4-methylthiophenoxy group, 4-ethylthiophenoxy group, 4-n-propylthiophenoxy group, 4-isopropylthiophenoxy group, 4-butoxyoxy group, 4-butoxyoxy group ter-butylthiophenoxy, group 4n-pentilt iophenoxy, 4-n-hexylthiophenoxy group, 2,4-dimethylthiophenoxy group, 3,4,5dimethylthiophenoxy group, 2- (1,2,4-triazol-1-yl) phenoxy group, group 3- (1,2,4 -triazolyl-1-yl) phenoxy, group 4- (1,2,4-triazol-1-yl) phenoxy, group 2- (3-isoxazolyl) phenoxy, group 3- (4isoxazolyl) phenoxy, group 4- (5 -isoxazolyl) phenoxy, group 2- (1-imidazolyl) phenoxy, group 3- (1imidazolyl) phenoxy, group 4- (1-imidazolyl) phenoxy, group 2- (2-benzothiazolyl) phenoxy, group 3 (2-benzothiazolyl) phenoxy, group 4- (2-benzothiazolyl) phenoxy, group 2- (2H-benzotriazol-2Petition 870190039560, of 26/04/2019, p. 139/876

131/854 il) phenoxy, group 3- (2H-benzotriazol-2-yl) phenoxy, group 4- (2H-benzotriazol-2-yl) phenoxy, group 2- (1-pyrrolyl) phenoxy, group 3- (1 -pyrrolyl) phenoxy, group 4- (1-pyrrolyl) phenoxy, group 2 (2-benzoxazolyl) phenoxy, group 3- (2-benzoxazolyl) phenoxy, group 4- (2-benzoxazolyl) phenoxy, group 2- (1- piperazinyl) phenoxy, group 3- (1-piperazinyl) phenoxy, group 4- (1piperazinyl) phenoxy, group 4- (4-methoxycarbonyl-1-piperazinyl) phenoxy, group 4- (4ethoxycarbonyl-1-piperazinyl) phenoxy, group 4 - (4-n-propoxycarbonyl-1-piperazinyl) phenoxy, group 4- (4-n-butoxycarbonyl-1-piperazinyl) phenoxy, group 4- (4-n-pentyloxycarbonyl-1piperazinyl) phenoxy, group 4- (4- n-hexyloxycarbonyl-1-piperazinyl) phenoxy, group 4- (4-benzyl-

1-piperazinyl) phenoxy, group 4- (4- (2-phenethyl) -1-piperazinyl) phenoxy, group 4- (4- (3-phenylpropyl) -1-piperazinyl) phenoxy, group 4- (4- (4-phenylbutyl) ) -1-piperazinyl) phenoxy, group 4 (4- (5-phenylpentyl) -1-piperazinyl) phenoxy, group 4- (4- (6-phenylexyl) -1-piperazinyl) phenoxy, group

4- [4- (2-fluorobenzyl) -1-piperazinyl] phenoxy, group 4- [4- (3-fluorobenzyl) -1 piperazinyl] phenoxy, group 4- [4- (4-fluorobenzyl) -1-piperazinyl] phenoxy, group 4- [4- (4-chlorobenzyl) -1-piperazinyl] phenoxy, group 4- [4- (3-chlorobenzyl) -1-piperazinyl] phenoxy, group

4- [4- (4-chlorobenzyl) -1-piperazinyl] phenoxy, group 4- [4- (2,3-dichlorobenzyl) -1 piperazinyl] phenoxy, group 4- [4- (2,4-dichlorobenzyl) - 1-piperazinyl] phenoxy, group 4- [4- (3,4dichlorobenzyl) -1-piperazinyl] phenoxy, group 4- [4- (3,5-dichlorobenzyl) -1 -piperazinyl] phenoxy, group 4- [4- (3,4,5-trichlorobenzyl) -1-piperazinyl] phenoxy, group 4- [4- (2-trifluoromethylbenzyl) 1-piperazinyl] phenoxy, group 4- [4- (3-trifluoromethylbenzyl) -1-piperazinyl] phenoxy , group 4- [4 (4-trifluoromethylbenzyl) -1-piperazinyl] phenoxy, group 4- [4- (4-methylbenzyl) -1 piperazinyl] phenoxy, group 4- [4- (3,4-dimethylbenzyl) -1 -piperazinyl] phenoxy, group 4- [4- (2,4,6trim eti Ibenzi l) -1 -piperazinyl] phenoxy, group 4- [4- (2-pentafluoroethylbenzyl) -1 - piperazinyl] phenoxy, group 4- [ 4- (3-pentafluoroethylbenzyl) -1-piperazinyl] phenoxy, group 4- [4 (4-pentafluoroethylbenzyl) -1 -piperazinyl] phenoxy, group 4- [4- (2-trifluoromethoxybenzyl) -1 piperazinyl] phenoxy, group 4 - [4- (3-trifluoromethoxybenzyl) -1-piperazinyl] phenoxy, group 4- [4 (4-trifluoromethoxybenzyl) -1 - piperazinyl] phenoxy, group 4- [4- (4-methoxybenzyl) -1 piperazinyl] phenoxy, group 4- [4- (3,4-dimethoxybenzyl) -1-piperazinyl] phenoxy, group 4- [4 (2.4 , 6-trimethoxybenzyl) -1-piperazinyl] phenoxy, group 4- [4- (2-pentafluoroethoxybenzyl) -1 piperazinyl] phenoxy, group 4- [4- (3-pentafluoroethoxybenzyl) -1-piperazinyl] phenoxy, group 4 [ 4- (4-pentafluoroethoxybenzyl) -1-piperazinyl] phenoxy, group 4- {4- [2- (4Petition 870190039560, from 26/04/2019, p. 140/876

132/854 trifluoromethoxyphenyl) ethyl] -1-piperazinyljphenoxy, trifluoromethoxyphenyl) propyl] -1-piperazinyljphenoxy, trifluoromethoxyphenyl) butyl] -1 -piperazinyljphenoxy, trifluoromethoxyphenyl) pentyl] -1 group

4_ {4_ [3_ (4_

4- {4- [4- (44- {4_ [5_ (44- {4- [6- (4trifluoromethoxyphenyl) hexyl] -1-piperaziniIJphenoxy, group 4- {4- [2- (4-trifluoromethylIphenyl) ethyl] -1 piperazinyljenoxy, group 4- {4- [3- (4-trifluoromethylphenyl) propyl] -1 -piperazinyljenoxy, group

4- {4- [4- (4-trifluoromethylphenyl) butyl] -1-piperazinyl} phenoxy, group

4_ {4_ [5_ (4_ trifluoromethylphenyl) pentyl] -1-piperazinyljphenoxy, group 4- {4- [6- (4-trifluoromethylphenyl) hexyl] 1 -piperazinyljphenoxy, group 2-piperidinophenoxy, group 3-piperidinophenoxy, group 4 2- (4-amino-1-piperidyl) phenoxy, group 3- (4-amino-1-piperidyl) phenoxy, group 4- (4-amino-1-piperidyl) phenoxy, group 4- (4-methylamino-1piperidyl) phenoxy , group 4- (4-ethylamino-1-piperidyl) phenoxy, group 4- (4-n-propylamino-1piperidyl) phenoxy, group 4- (4-dimethylamino-1-piperidyl) phenoxy, group 4- (4-diethylamino -1piperidyl) phenoxy, group 4- (4-di-n-propylamino-1-piperidyl) phenoxy, group 4- (4-phenylamino1-piperidyl) phenoxy, group 4- [4- (N-phenyl-N-methylamino) -1-piperidyl] phenoxy, group 4- [4- (2-fluorophenylamino) -1 -piperidyl] phenoxy, group 4- [4- (3-fluorophenylamino) -1 -piperidyl] phenoxy, group 4- [4- (4- fluorophenylamino) -1-piperidyl] phenoxy, group 4- [4- (2-chlorophenylamino) -1piperidyl] phenoxy, group 4- [4- (3-chlorophenylamino) -1-piperidyl)] phenoxy, group 4- [4- (4-chlorophenylamino) -1-piperidyl] phenom xi, group 4- [4- (2,3-dichlorophenylamino) -1-piperidyl] phenoxy, group 4- [4- (2,4-dichlorophenylamino) -1-piperidyl] phenoxy, group 4- [4- (3 , 4dichlorophenylamino) -1-piperidyl] phenoxy, group 4- [4- (3,5-dichlorophenylamino) -1 piperidyl] phenoxy, group 4- [4- (2-trifluoromethylphenylamino) -1-pipendyl] phenoxy, group 4 - [4- (2-methylphenylamino) -1-piperidyl] phenoxy, group 4- [4- (2,3-dimethylphenylamino) -1 -piperidyl] phenoxy, group 4- [4- (2-trifluoromethylphenylamino) -1-pipendyl] phenoxy, group 4- [4- (2,4,6trimethylphenylamino) -1-piperidyl] phenoxy, group 4- [4- (4-trifluoromethylphenylamino) -1 piperidyl] phenoxy, group 4- [4- (2-pentafluoroethylphenylamino ) -1-piperidyl] phenoxy, group 4- [4 (3-pentafluoroethylphenylamino) -1 -piperidyl] phenoxy, group 4- [4- (4pentafluoroethylphenylamino) -1 -piperidyl] phenoxy, group 4- [4- (2 -trifluoromethoxyphenylamino) -1 piperidyl] phenoxy, group 4- [4- (2-methoxyphenylamino) -1-piperidyl] phenoxy, group 4- [4- (2,3dimethoxyphenylamino) -1 -piperidyl] phenoxy, group 4- [ 4- (2,4,6-trimethoxyphenylamino) -1 Petition 870190039 560, of 04/26/2019, p. 141/876

133/854 piperidyl] phenoxy, group 4- {4- [N-methyl-N- (2,4,6-trimethoxyphenylamino)] - 1-piperidyl} phenoxy, group 4- {4- [N-methyl-N- (3,4-dimethylphenylamino)] - 1-piperidyl} phenoxy, group 4- [4- (3trifluoromethoxyphenylamino) -1 -piperidyl] phenoxy, group 4- [4- (4-trifluoromethoxyphenylamino) -1 piperidyl] phenoxy, group 4 - [4- (2-pentafluoroethoxyphenylamino) -1-piperidyl] phenoxy, group 4 [4- (3-pentafluoroethoxyphenylamino) -1 -piperidyl] phenoxy, group 4- [4- (4pentafluoroethoxyphenylamino) -1-piperidyl] phenoxy, 2-carbamoylphenoxy group, 3-carbamoylphenoxy group, 4-carbamoylphenoxy group or the like.

[0213] Examples of a phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent), halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) include a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a phenoxy group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent), halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent), by example, a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, group 2- iodophenyl, 3iodophenyl group, 4-iodophenyl group, 2,3-difluorophenyl group, 3,4-difluorophenyl group, group

3.5- difluorophenyl, 2,4-difluorophenyl group, 2,6-difluorophenyl group, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group , 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl group, group

3.4.5- trichlorophenyl, group 2,4,6-trifluorophenyl, group 2,3,4,5,6-pentafluorophenyl, group

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134/854

2,4,6-trichlorophenyl, 2-fluoro-4-chlorophenyl group, 2-fluoro-4-bromophenyl group, 3fluoro-4-chlorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, group

2-methyl-3-chlorophenyl, 3-methyl-4-chlorophenyl group, 2-chloro-4-methylphenyl group, 2methyl-3-fluorophenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4trifluoromethylphenyl group, 2-pentafluoro group , 3-pentafluoroethylphenyl group, 4pentafluoroethylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 4isopropylphenyl group, 2-ter-butylphenyl group, 3-ter-butylphenyl group, 4-ter-butylphenyl group, 2-sec-butyl group group 3-sec-butylphenyl, group 4-sec-butylphenyl, group 2-nheptafluoropropylphenyl, group 3-n-heptafluoropropylphenyl, group 4-nheptafluoropropylphenyl, group 4-pentylphenyl, group 4-hexylphenyl, group 4-fluoro-phenyl -chloro-3-fluorophenyl, 2,3,4-trichlorophenyl group, 4-n-butylphenyl group, 2,4-dimethylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,6-dimethylphenyl group, group 3,5-dimethylphenyl, 2,5-dimethylphenyl group, 2,4,6trimethylphenyl group, 3,5-ditrifluoromethylphenyl group, 4-n-butoxife group nila, 2,4-dimethoxyphenyl group, 2,3-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 3,5-ditrifluoromethoxyphenyl group, 2,4,6-trimethoxyphenyl group, group 3- chloro-4-methoxyphenyl, group 2-chloro-4-trifluoromethoxyphenyl, group 3-methyl-4-fluorophenyl, group 4-bromo-3-trifluoromethylphenyl, group 2-methylphenyl, group 3-methylphenyl, group 4-methoxyphenyl, group 2 -methoxy-3-chlorophenyl, group 2-fluoro-

3-methoxyphenyl, group 2-fluoro-4-methoxyphenyl, group 2,6-dimethoxyphenyl, group 2trifluoromethoxyphenyl, group 3-trifluoromethoxyphenyl, group 4-trifluoromethoxyphenyl, group 2-pentafluoroethoxyphenylphenoxyphenoxyphenoxyphenoxyphenoxyphenyl, group 4 , 3-isopropoxyphenyl group, 4isopropoxyphenyl group, 2-ter-butoxyphenyl group, 3-ter-butoxyphenyl group, 4-terbutoxyphenyl group, 2-sec-butoxyphenyl group, 3-sec-butoxyphenyl group, 4-secbutoxyphenyl group, group 2- n-heptafluoropropoxyphenyl, group 3-n-heptafluoropropoxyphenyl, group 4-n-heptafluoropropoxyphenyl, group 4-pentyloxyphenyl, group 4-hexyloxyphenyl, group 2-phenoxyphenyl, group 3-phenoxyphenyl, group 4-phenoxyphenyl, group 2-phenoxyphenyl, 2-phenoxyphenyl group , group 2- (3-chlorophenoxy) phenyl, group 2- (4-chlorophenoxy) phenyl, group 3 (2-chlorophenoxy) phenyl, group 3- (3-chlorophenoxy) phenyl, group 3- (4-chlorophenoxy) phenyl, group

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135/854

4- (2-chlorophenoxy) phenyl, group 4- (3-chlorophenoxy) phenyl, group 4- (4-chlorophenoxy) phenyl, group 2- (2-trifluoromethylphenoxy) phenyl, group 2- (2-methylphenoxy) phenyl, trifluoromethylphenoxy ) phenyl, trifluoromethylphenoxy) phenyl, trifluoromethylphenoxy) phenyl, trifluoromethylphenoxy) phenyl, trifluoromethoxyphenoxy) phenyl, trifluoromethoxyphenoxy) phenyl, dimethylphenoxy) phenyl, group 2- (2,4,6-trimethylphenoxy) phenyl , 4,5-trimethoxyphenoxy) phenyl, trifluoromethoxyphenoxy) phenyl, group 3- (3-trifluoromethoxyphenoxy) phenyl, group trifluoromethoxyphenoxy) phenyl, group 4- (2-trifluoromethoxyphenoxy) phenyl, trifluoromethoxyphenoxy) phenyl, group 4- ( or similar. [0214] A C3-8 cycloalkyl group - C1-6 alkoxy is a group containing a cyclic alkyl having 3 to 8 carbon atoms and a group having 1 to 6 carbon atoms, examples of which include group group group group group group

2- (4-trifluoromethylphenoxy) phenyl,

3- (3-trifluoromethylphenoxy) phenyl,

4- (2-trifluoromethylphenoxy) phenyl,

4- (4-trifluoromethylphenoxy) phenyl,

2- (3-trifluoromethoxyphenoxy) phenyl,

2- (4-methoxyphenoxy) phenyl, group group group group group group group group group group group group

2- (3-

3- (2-

3- (4-

4- (3-

2- (2-

2- (4-

2- (2.42- (3.4-

3- (2-

3- (4-

4- (3-alkoxy group a cyclopropylmethoxy group, 2-cyclopropylethoxy group, 3-cyclopropylpropoxy group, group

4-cyclopropylbutoxy, 5-cyclopropylpentyloxy group, 6-cyclopropylexyloxy group, cyclobutylmethoxy group, 2-cyclobutylethoxy group, 3-cyclobutylpropoxy group, 4cyclobutylbutoxy group, 5-cyclobutylpentyloxy group, 6-cyclobutyloxy group, cyclooxymethyl group -cyclopentylpropoxy, 4cyclopentylbutoxy group, 5-cyclopentylpentyloxy group, 6-cyclopentylexyloxy group, cyclohexylmethoxy group, 2-cyclohexylethoxy group, 3-cyclohexylpropoxy group, 4-cyclohexylbutoxy group, 5-cyclohexylpentyl group -hexylexyloxy, cycloheptylmethoxy group, 2-cycloheptyloxy group, 3-cycloheptylpropoxy group, 4-cycloheptylbutoxy group, 5-cycloheptylpentyloxy group, 6-cycloheptyloxyloxy group, cyclooctylmethoxy group, 2-cyclooctyloxy group, 2-cyclooctyloxy group cyclooctylpropoxy, 4cyclooctylbutoxy group, 5-cyclooctylpentyloxy group, 6-cyclooctyloxyoxy group or the like. [0215] A phenylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom,

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136/854 a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) is a group containing aniline, N-C6 alkylaniline or N-phenyl C1-6 alkylaniline which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen, an unsubstituted or substituted C1-6 alkyl group and an unsubstituted or substituted C1-6 alkoxy group by halogen, and a carbonyl group, examples of which include a phenylcarbamoyl group, 2fluorophenylcarbamoyl group, 3-fluorophenylcarbamoyl group, 4-fluorophenylcarbamoyl group, 2-chlorophenylcarbamoyl group, 3-chlorophenylcarbamoyl group, group 4 3-bromophenylcarbamoyl, group 4-bromophenylcarbamoyl, group 2-iodophenylcarbamoyl, group 3iodophenylcarbamoyl, group 4-iodophenylcarbamoyl, group 2,3-difluorophenyl carbamoyl, group 3,4-difluorophenylcarbamoyl, group 3,5-difluorophenylcarbamoyl, group

2,4difluorophenylcarbamoyl, group

2,6-difluorophenylcarbamoyl, group

2,3dichlorophenylcarbamoyl, 3,4-dichlorophenylcarbamoyl group, 3,5dichlorophenylcarbamoyl group, 2,4-dichlorophenylcarbamoyl group, 2,6dichlorophenylcarbamoyl group, 3,4,5-trifluorophenylcarbamoyl group, 2,3,4,5,6 pentafluyl group 3,4,5-trichlorophenylcarbamoyl, group 2,4,6 trifluorophenylcarbamoyl, group 2,4,6-trichlorophenylcarbamoyl, group 2methylphenylcarbamoyl, group 3-methylphenylcarbamoyl, group 4-methylphenylcarbamoyl, group 2-methyl-3-methyl-3-methyl-3-group methyl-4-chlorophenylcarbamoyl, group 2chloro-4-methylphenylcarbamoyl, group 2-methyl-3-fluorophenylcarbamoyl, group 2 trifluoromethylphenylcarbamoyl, group 3-trifluoromethylphenylcarbamoyl, group N-methyl-fluoryl-N-methyl-N-group , N- (3-fluorophenyl) -Nmethylcarbamoyl group, N- (4-fluorophenyl) -N-methylcarbamoyl group, N- (2-chlorophenyl) -Nmethylcarbamoyl group, N- (3-chlorophenyl) -N-methylcarbamoyl group, group N- (4-chlorophenyl) -Nmethylcarbamoyl, group N- (4-bromo phenyl) -N-methylcarbamoyl, group N- (2-iodophenyl) -Nmethylcarbamoyl, group N- (3-iodophenyl) -N-methylcarbamoyl, group N- (4-iodophenyl) -Nmethylcarbamoyl, group N- (2,3- difluorophenyl) -N-methylcarbamoyl, group N- (3,4difluorophenyl) -N-methylcarbamoyl, group N- (3,5-difluorophenyl) -N-methylcarbamoyl, group

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137/854

N- (2,4-difluorophenyl) -N-methylcarbamoyl, group N- (2,6-difluorophenyl) -N-methylcarbamoyl, group N- (2,3-dichlorophenyl) -N-methylcarbamoyl, group N- (3, 4-dichlorophenyl) -Nmethylcarbamoyl, group N- (3,5-dichlorophenyl) -N-methylcarbamoyl, group N- (2,4dichlorophenyl) -N-methylcarbamoyl, group N- (2,6-dichlorophenyl) -N-methylcarbamoyl, group N (3,4,5-trifluorophenyl) -N-methylcarbamoyl, group N- (3,4,5-trichlorophenyl) -Nmethylcarbamoyl, group N- (2,4,6-trifluorophenyl) -N-methylcarbamoyl, group N - (2,4,6tnchlorophenyl) -N-methylcarbamoyl, group N- (2-methylphenyl) -N-methylcarbamoyl, group N- (3-methylphenyl) -N-methylcarbamoyl, group N- (4-methylphenyl) -N-methylcarbamoyl, group N- (2methyl-3-chlorophenyl) -N-methylcarbamoyl, group N- (3-methyl-4-chlorophenyl) -Nmethylcarbamoyl, group N- (2-chloro-4-methylphenyl) -N-methylcarbamoyl, group N- (2-methyl-3fluorophenyl) -N-methylcarbamoyl, group N- (2-trifluoromethylphenyl) -N-methylcarbamoyl, group N- (4-trifluoromethylphenyl) -N-methylcarbamoyl, group N-benzyl-N-phenylcarbamoyl, group N zyl-N- (2-fluorophenyl) carbamoyl, group N-benzyl-N- (3-fluorophenyl) carbamoyl, group N-benzyl-N- (4-fluorophenyl) carbamoyl, group N-benzyl-N- (2-chlorophenyl) ) carbamoyl, N-benzyl-N- (3-chlorophenyl) carbamoyl group, N-benzyl-N- (4-chlorophenyl) carbamoyl group, N-benzyl-N- (2-bromophenyl) carbamoyl group, N-benzyl- group N- (3-bromophenyl) carbamoyl, N-benzyl-N- (4-bromophenyl) carbamoyl group, N-benzyl-N- (2iodophenyl) carbamoyl group, N-benzyl-N- (3-iodophenyl) carbamoyl group, group N-benzyl-N- (4iodophenyl) carbamoyl, group N-benzyl-N- (2,3-difluorophenyl) carbamoyl, group N-benzylN- (3,4-difluorophenyl) carbamoyl, group N-benzyl-N- (3 , 5-difluorophenyl) carbamoyl, N-benzyl-N- (2,4-difluorophenyl) carbamoyl group, N-benzyl-N- (2,6difluorophenyl) carbamoyl group, N-benzyl-N- (2,3-dichlorophenyl group) ) carbamoyl, Nbenzyl-N- (3,4-dichlorophenyl) carbamoyl group, N-benzyl-N- (3,5-dichlorophenyl) carbamoyl group, N-benzyl-N- (2,4-dichlorophenyl) carbamoyl group N-benzyl-N- (2,6dichlorophenyl) carbamoyl, group o N-benzyl-N- (3,4,5-trifluorophenyl) carbamoyl, Nbenzyl-N- (3,4,5-trichlorophenyl) carbamoyl group, N-benzyl-N- (2,4,6trifluorophenyl) carbamoyl group, N-benzyl-N- (2,4,6-trichlorophenyl) carbamoyl group, Nbenzyl-N- (2-methylphenyl) carbamoyl group, N-benzyl-N- (3-methylphenyl) carbamoyl group, Nbenzyl-N- ( 4-methylphenyl) carbamoyl, N-benzyl-N- (2-methyl-3-chlorophenyl) carbamoyl group, N-benzyl-N- (3-methyl-4-chlorophenyl) carbamoyl group, N-benzyl-N- ( 2-chloro-4Petition 870190039560, of 26/04/2019, p. 146/876

138/854 methylphenyl) carbamoyl, N-benzyl-N- (2-methyl-3-fluorophenyl) carbamoyl group, Nbenzyl-N- (2-trifluoromethylphenyl) carbamoyl group, N-benzyl-N- (3trifluoromethylphenyl) carbamoyl group, group N-benzyl-N- (4-trifluoromethylphenyl) carbamoyl group, 2-pentafluoroetilfenilcarbamoíla group, 3-pentafluoroetilfenilcarbamoíla, 4pentafluoroetilfenilcarbamoíla group, 2-isopropilfenilcarbamoíla group, 3isopropilfenilcarbamoíla, 4-isopropilfenilcarbamoíla group, 2-terbutilfenilcarbamoíla group, 3-terbutilfenilcarbamoíla , group 4-ter-butylphenylcarbamoyl, group 2-sec-butylphenylcarbamoyl, group 3-sec-butylphenylcarbamoyl, group 4-secbutilphenylcarbamoyl, group 2-n-heptafluoropropylphenylcarbamyl, group 3-nheptafylpilfilfilfilfilfilfilfilfilfilfilfilfilfil 4-hexylphenylcarbamoyl, 2,4-dimethylphenylcarbamoyl group, 2,4,6-trimethylphenylcarbamoyl group, 3,4-dimethoxyphenylcarbamoyl group, 3,4,5trimethoxy group ifenylcarbamoyl, 2-methoxyphenylcarbamoyl group, 3methoxyphenylcarbamoyl group, 4-methoxyphenylcarbamoyl group, 2-methoxy-3-chlorophenylcarbamoyl group, 2-fluoro-3-methoxyphenylcarbamoyl group, 2-fluoro-methoxyphenylcarbamoyl group, 2-fluoro-methoxy-4-fluoro-methoxy-4-group 4trifluorofenilcarbamoíla, 3,4,5-trifluorofenilcarbamoíla group, 2trifluorometoxifenilcarbamoíla group, 3-trifluorometoxifenilcarbamoíla, 4trifluorometoxifenilcarbamoíla group, 2-pentafluoroetoxifenilcarbamoíla group, 3pentafluoroetoxifenilcarbamoíla, 4-pentafluoroetoxifenilcarbamoíla group, 2isopropoxifenilcarbamoíla group, 3-isopropoxifenilcarbamoíla, 4 isopropoxifenilcarbamoíla group butoxifenilcarbamoíla group, butoxyphenylcarbamoyl, butoxyphenylcarbamoyl, group

2-ter-butoxyphenylcarbamoyl,

4-ter-butoxyphenylcarbamoyl,

3-sec-butoxyphenylcarbamoyl, group group group

3-ter2-sec4-secgroup group 2-n-heptafluoropropoxyphenylcarbamoyl, group 3-nheptafluoropropoxyphenylcarbamoyl, group 4-n-heptafluoropropoxyphenylcarbamoyl, group 4-n-pentyloxyphenylcarbamoyl, group 4-n-group-hexane-n-group-4-n-group. [0216] Examples of a naphthyloxy group (which can be substituted on the naphthalene ring by at least one C1-6 alkyl group as a substituent) include a naphthyloxy group (which can be substituted on the naphthalene ring by 1 to 3 C1- alkyl groups 6 as one

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139/854 substituent), for example, a 1-naphthyloxy group, 2-naphthyloxy, 2-methyl-1-naphthyloxy group, 3-methyl-1-naphthyloxy group, 4-methyl-1-naphthyloxy group, 5-methyl group -1-naphthyloxy, 6methyl-1-naphthyloxy group, 7-methyl-1-naphthyloxy group, 8-methyl-1-naphthyloxy group, 1-methyl-2-naphthyloxy group, 5-methyl-2-naphthyloxy group, 4-ethyl group -1-naphthyloxy, 5-ethyl-1-naphthyloxy group,

6-ethyl-1-naphthyloxy, group 1-ethyl-2-naphthyloxy, group 5-ethyl-2-naphthyloxy, group 5-n-propyl-1 naphthyloxy, group 6-n-propyl-1-naphthyloxy, group 1 - n-propyl-2-naphthyloxy, group 5-n-propyl-2-naphthyloxy, group 5-n-butyl-1-naphthyloxy, group 6-n-butyl-1-naphthyloxy, group 1-n-butyl-2-naphthyloxy, group 5 -n-butyl-1-naphthyloxy, 5-n-pentyl-1-naphthyloxy group, 6-n-pentyl-1-naphthyloxy group, 1-n-pentyl-2-naphthyloxy group, 5-n-pentyl-2-naphthyloxy group , 5-n-hexyl-1-naphthyloxy group, 6-n-hexyl-1-naphthyloxy group, 1-n-hexyl-2-naphthyloxy group, 5-n-hexyl-2-naphthyloxy group, 2,4-dimethyl-1- group naphthyloxy, 4,6,7-trimethyl-2-naphthyloxy group or the like. [0217] Examples of a 2,3-dihydrobenzofuryloxy group (which can be substituted on the 2,3-dihydrobenzofuran ring by at least one selected from a group consisting of a C1-6 alkyl group and an oxo group) include a group 2 , 3-dihydrobenzofuryloxy (which can be substituted on the 2,3-dihydrobenzofuran ring by 1 to 3 groups selected from a group consisting of a C1-6 alkyl group and an oxo group), for example, a 2,3- dihydrobenzofuran-3-yloxy, 2,3-dihydrobenzofuran-4-yloxy group, 2,3-dihydrobenzofuran-5-yloxy group, 2,3-dihydrobenzofuran-6-yloxy group, 2,3 group group group group group group

2-oxo-2,3-dihydrobenzofuran-3-yloxy,

2-oxo-2,3-dihydrobenzofuran-5-yloxy,

2-oxo-2,3-dihydrobenzofuran-7-yloxy,

3-oxo-2,3-dihydrobenzofuran-4-yloxy,

3-oxo-2,3-dihydrobenzofuran-6-yloxy, group group group group group

2-oxo-2,3-

2- oxo-2,3-

3- oxo-2,3-

3-oxo-2,33-oxo-2,3dihydrobenzofuran-7-yloxy, dihydrobenzofuran-4-yloxy, dihydrobenzofuran-6-yloxy, dihydrobenzofuran-2-yloxy, dihydrobenzofuran-5-yloxy, dihydrobenzofuran-7-yloxy, group 2 -methyl-2,3-dihydrobenzofuran-3-yloxy, 2-methyl-2,3dihydrobenzofuran-4-yloxy group, 2-methyl-2,3-dihydrobenzofuran-5-yloxy group, 2-methyl-2,3dihydrobenzofuran- group 6-yloxy, dihydrobenzofuran-3-yloxy, dihydrobenzofuran-5-yloxy, dihydrobenzofuran-7-yloxy, 4-methyl-2,3-dihydrobenzofuran-3-yloxy group, 5-methyl-2,3dihydrobenzofuran-4-yloxy group, 4-methyl-2,3-dihydrobenzofuran-5-yloxy group, 4-methyl-2,3 group group group group

2-methyl-2,3-dihydrobenzofuran-7-yloxy,

2-ethyl-2,3-dihydrobenzofuran-4-yloxy,

2-ethyl-2,3-dihydrobenzofuran-6-yloxy, group group group

2-ethyl-2,32-ethyl-2,32-ethyl-2,3 Petition 870190039560, of 26/04/2019, p. 148/876

140/854 dihydrobenzofuran-6-yloxy, 4-methyl-2,3-dihydrobenzofuran-7-yloxy group, 6-methyl-2,3dihydrobenzofuran-3-yloxy group, 6-methyl-2,3-dihydrobenzofuran-4- iloxy, 6-methyl-2,3-dihydrobenzofuran-5-yloxy group, 6-methyl-2,3-dihydrobenzofuran-7-yloxy group, 7-methyl-2,3dihydrobenzofuran-3-yloxy group, 7-methyl-2 group, 3-dihydrobenzofuran-4-yloxy, 7-methyl-2,3-dihydrobenzofuran-5-yloxy group, 7-methyl-2,3-dihydrobenzofuran-6-yloxy group, 2-n-propyl-

2,3-dihydrobenzofuran-5-yloxy, 2-n-propyl-2,3-dihydrobenzofuran-6-yloxy group, 2-nbutyl-2,3-dihydrobenzofuran-5-yloxy group, 2-n-butyl-2 group , 3-dihydrobenzofuran-6-yloxy, 2n-pentyl-2,3-dihydrobenzofuran-5-yloxy group, 2-n-pentyl-2,3-dihydrobenzofuran-6-yloxy group, 2-n-hexyl-2 group, 3-dihydrobenzofuran-5-yloxy, 2-n-hexyl-2,3-dihydrobenzofuran-6yloxy group, 2,2-dimethyl-2,3-dihydrobenzofuran-5-yloxy group, 2,2,4-trimethyl-2 group , 3dihydrobenzofuran-5-yloxy, 3-oxo-4-methyl-2,3-dihydrobenzofuran-5-yloxy group, 2,2dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yloxy group or the like.

[0218] Examples of a benzothiazolyloxy group (which can be substituted on the benzothiazole ring by at least one C 1 -alkyl group) include a benzothiazolyloxy group (which can be substituted on the benzothiazole ring by 1 to 3 C 1 -alkyl groups), for example, a 2-benzothiazolyloxy group, 4-benzothiazolyloxy group, 5benzothiazolyloxy group, 6-benzothiazolyloxy group, 7-benzothiazolyloxy group, 2-methyl-5benzothiazolyloxy group, 4-methyl-5-benzothiazolyloxy group benzothiazolyloxy, 7-methyl-5-benzothiazolyloxy group, 4-ethyl-2-benzothiazolyloxy group, 5-ethyl-2benzothiazolyloxy group, 6-ethyl-4-benzothiazolyloxy group, 7-ethyl-6-benzothiazolyloxy group, group 4n 7-benzothiazolyloxy, 5-n-propyl-2-benzothiazolyloxy group, 6-n-propyl-2benzothiazolyloxy group, 7-n-propyl-5-benzothiazolyloxy group, 4-n-butyl-5-benzothiazolyloxy group, 5-n group -butyl-2-benzothiazolyloxy, 6-n-butyl-2-benzothiazolyloxy group, 7-n-butyl-4benzothiazolyloxy group, 4-n-pentyl-6-benzothiazoli group loxy, 5-n-pentyl-7benzothiazolyloxy group, 6-n-pentyl-2-benzothiazolyloxy group, 7-n-pentyl-2benzothiazolyloxy group, 4-n-hexyl-2-benzothiazolyloxy group, 5-n-hexyl-2 group -benzothiazolyloxy, 6-n-hexyl-2-benzothiazolyloxy group, 7-n-hexyl-2-benzothiazolyloxy group, 2,4dimethyl-5-benzothiazolyloxy group, 2,4,6-trimethyl-5-benzothiazolyloxy group or the like.

[0219] Examples of a 1,2,3,4-tetrahydronaphthoxy group (which can be substituted on the 1,2,3,4-tetrahydronaphthalene ring by at least one oxo group as a substituent)

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141/854 include a 1,2,3,4-tetrahydro-1-naphthyloxy group, 1,2,3,4-tetrahydro-2-naphthyloxy group, group

1,2,3,4-tetrahydro-6-naphthyloxy, group 1,2,3,4-tetrahydro-5-naphthyloxy, group 1,2,3,4-tetrahydro-1-oxo-5-naphthyloxy, group 1,2 , 3,4-tetrahydro-2-oxo-3-naphthyloxy, group 1,2,3,4-tetrahydro-1 oxo-6-naphthyloxy, group 1,2,3,4-tetrahydro-3-oxo-5- naphthyloxy, group 1,2,3,4-tetrahydro-4-oxo-

6-naphthyloxy, 1,2,3,4-tetrahydro-2-oxo-7-naphthyloxy group, 1,2,3,4-tetrahydro-1-oxo-8naphthoxy group or the like.

[0220] Examples of a 1,3-benzoxathiolaniloxy group (which can be substituted on the 1,3-benzoxathiolane ring by at least one oxo group as a substituent) include a 1,3-benzoxathiolane-4-yloxy group, group 1, 3-benzoxathiolan-5-yloxy, 1,3benzoxathiolan-6-yloxy group, 1,3-benzoxathiolan-7-yloxy group, 2-oxo-1,3benzoxathiolane-5-yloxy group, 2-oxo-1,3- group benzoxathiolane-6-yloxy, group 2-oxo-1,3benzoxathiolane-7-yloxy or the like.

[0221] Examples of an isoquinolyloxy group include an isoquinolin-1-yloxy group, isoquinolin-3-yloxy group, isoquinoline-4-yloxy group, isoquinoline-5-yloxy group, isoquinoline-6-yloxy group, isoquinolin-7-group iloxy, isoquinoline-8-yloxy group or the like.

[0222] Examples of a pyridyloxy group include 2-pyridyloxy group, 3-pyridyloxy group or 4-pyridyloxy group.

[0223] Examples of a quinolyloxy group (which can be substituted on the quinoline ring by at least one C1-6 alkyl group as a substituent) include a quinolyloxy group (which can be substituted on the quinoline ring by 1 to 3 C1-6 alkyl groups) 6 as a substituent), for example, a 2-quinolyloxy group, 3-quinolyloxy group, 4-quinolyloxy group, 5-quinolyloxy group, 6-quinolyloxy group, 7-quinolyloxy group, group

8-quinolyloxy, 3-methyl-2-quinolyloxy group, 4-methyl-2-quinolyloxy group, 5-methyl-2-quinolyloxy group, quinolyloxy, quinolyloxy, quinolyloxy, quinolyloxy, quinolyloxy, quinolyloxy, group group group group group group group group

6- methyl-2-quinolyloxy,

4-methyl-3-quinolyloxy,

7-methyl-3-quinolyloxy,

3-methyl-4-quinolyloxy,

7-methyl-4-quinolyloxy,

4- methyl-5-quinolyloxy,

7-methyl-5-quinolyloxy, group group group group group group group group

7-methyl-2-quinolyloxy,

5-methyl-3-quinolyloxy,

8-methyl-3-quinolyloxy,

5-methyl-4-quinolyloxy,

8-methyl-4-quinolyloxy,

3-methyl-5-quinolyloxy,

8-methyl-5-quinolyloxy, group group group group group group group group

2-methyl-36-methyl-32-methyl-46-methyl-42-methyl-56-methyl-52-methyl-6Petition 870190039560, of 26/04/2019, p. 150/876

142/854 group group group group group

4-methyl-6-quinolyloxy,

7-methyl-6-quinolyloxy,

4-methyl-7-quinolyloxy,

3-methyl-7-quinolyloxy,

4- methyl-8-quinolyloxy, group group group group group

5-methyl-6-quinolyloxy,

8-methyl-6-quinolyloxy,

5-methyl-7-quinolyloxy,

8-methyl-7-quinolyloxy,

5-methyl-8-quinolyloxy, group group group group group

2-methyl-76-methyl-72-methyl-86-methyl-8quinolyloxy, quinolyloxy, quinolyloxy, quinolyloxy, quinolyloxy, quinolyloxy, group 7-methyl-8-quinolyloxy, group 3-methyl-8-quinolyloxy, group 2.5 -dimethyl-8 quinolyloxy, 6,7-dimethyl-4-quinolyloxy group, 4,6,7-trimethyl-5-quinolyloxy group, compounds substituted by an ethyl group, n-propyl group, n-butyl group, n- group pentyl or n-hexyl group in place of the methyl group of these compounds or the like. [0224] Examples of a dibenzofuryloxy group include a 1-dibenzofuryloxy group, 2-dibenzofuryloxy group, 3-dibenzofuryloxy group, 4-dibenzofuryloxy group, 5dibenzofuryloxy group, 6-dibenzofuryloxy group, 6-dibenzofuryloxy group, 7-dibenzyl group .

[0225] Examples of a 2H-chromenyloxy group (which can be substituted on the ring

2H-chromene by at least one oxo group as a substituent) include a group

4- (2H) chromenyloxy, group 5- (2H) chromenyloxy, group 6- (2H) chromenyloxy, group 7 (2H) chromenyloxy, group 8- (2H) chromenyloxy, group 2-oxo-4- (2H) chromenyloxy, 2oxo-5- (2H) chromenyloxy group, 2-oxo-6- (2H) chromenyloxy group, 2-oxo-7 (2H) chromenyloxy group, 2-oxo-8- (2H) chromenyloxy group or the like.

[0226] Examples of a benzisoxazolyloxy group include a 3benzisoxazolyloxy group, 4-benzisoxazolyloxy group, 5-benzisoxazolyloxy group, 6benzisoxazoloxy group, 7-benzisoxazolyloxy group or the like.

[0227] Examples of a quinoxalyloxy group include a 2-quinoxalyloxy group, 5-quinoxalyloxy group, 6-quinoxalyloxy group or the like.

[0228] Examples of a 2,3-dihydro-1 H-indenyloxy group (which can be substituted on the 2,3-dihydro-1 H-indene ring by at least one oxo group as a substituent) include a 2,3 group -dihydro-1 H-inden-1-yloxy, group 2,3-dihydro-1 H-inden-2-yloxy, group

2,3-dihydro-1 H-inden-3-yloxy, group 2,3-dihydro-1 H-inden-4-yloxy, 2,3-dihydro-1 Hinden-5-yloxy, group 2,3- dihydro-1 H-inden-6-yloxy, group 2,3-dihydro-1 H-inden-7-yloxy, group 2,3-dihydro-1-oxo-1 H-inden-2-yloxy, group 2, 3-dihydro-1-oxo-1 H-inden-3-yloxy, group

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143/854

2,3-dihydro-1-oxo-1 H-inden-4-yloxy, 2,3-dihydro-1-oxo-1 H-inden-5-yloxy group, 2,3dihydro-1-oxo-1 H group -inden-6-yloxy, 2,3-dihydro-1-oxo-1 H-inden-7-yloxy group or the like.

[0229] Examples of a benzofurazaniloxy group include, for example, a group

4-benzofurazaniloxy, 5-benzofurazanyloxy group or the like.

[0230] A C2-6 phenyl alkenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and a group C1-6 alkoxy unsubstituted or substituted by halogen) is a group containing an unsubstituted or substituted by 1 to 5 phenyl group, preferably 1 to 3 groups selected from a group consisting of a halogen atom, an alkyl group C1-6 unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen, and an alkenyl group containing from 2 to 6 carbon atoms and having at least one double bond. These groups can be found in the trans or cis form and both forms are of course included. These C2-6 phenyl alkenyl groups include, for example, a 3 (2-fluorophenyl) -2-propenyl group, 3- (3-fluorophenyl) -2-propenyl group, 3- (4-fluorophenyl) 2-propenyl group, group 3- (2,3-difluorophenyl) -2-propenyl, group 3- (2,3,4,5,6pentafluorophenyl) -2-propenyl, group 3- (2,4-difluorophenyl) -2-propenyl, group 3- (3,4difluorophenyl) -2-propenyl, group 3- (3,5-difluorophenyl) -2-propenyl, group 3- (2-chlorophenyl) -2-propenyl, group 3- (3-chlorophenyl) -2-propenyl , group 3- (4-chlorophenyl) -2propenyl, group 3- (2,3-dichlorophenyl) -2-propenyl, group 3- (2,4-dichlorophenyl) -2-propenyl, group 3- (3,4- dichlorophenyl) -2-propenyl, group 3- (3,5-dichlorophenyl) -2-propenyl, group 3 (2-bromophenyl) -2-propenyl, group 3- (3-bromophenyl) -2-propenyl, group 3- (4bromophenyl) -2-propenyl, group 3- (2-methylphenyl) -2-propenyl, group 3- (3-methylphenyl) -2propenyl, group 3- (4-methylphenyl) -2-propenyl, group 3- (2 -trifluoromethylphenyl) -2-propenyl, group 3- (2-fluoro-4-bromophenyl) -2-propenyl, group 3- (4-chloro-3-fluorophenyl) -2propenyl, group 3 - (2,3,4-trichlorophenyl) -2-propenyl, group 3- (2,4,6-trichlorophenyl) -2propenyl, group 3- (4-isopropylphenyl) -2-propenyl, group 3- (4-n -butylphenyl) -2-propenyl, group 3- (2,4-dimethylphenyl) -2-propenyl, group 3- (2,3-dimethylphenyl) -2-propenyl, group 3 (2,6-dimethylphenyl) -2- propenyl, group 3- (3,5-dimethylphenyl) -2-propenyl, group 3- (2,5

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144/854 dimethylphenyl) -2-propenyl, group 3- (2,4,6-trimethylphenyl) -2-propenyl, group 3- (3,5ditrifluoromethylphenyl) -2-propenyl, group 3- (4-n-butoxyphenyl) -2-propenyl, group 3- (2,4dimethoxyphenyl) -2-propenyl, group 3- (2,3-dimethoxyphenyl) -2-propenyl, group 3- (2,6dimethoxyphenyl) -2-propenyl, group 3- ( 3,5-dimethoxyphenyl) -2-propenyl, group 3- (2,5dimethoxyphenyl) -2-propenyl, group 3- (3,5-ditrifluoromethoxyphenyl) -2-propenyl, group 3- (3chloro-4-methoxyphenyl) - 2-propenyl, group 3- (2-chloro-4-trifluoromethoxyphenyl) -2-propenyl, group 3- (3-methyl-4-fluorophenyl) -2-propenyl, group 3- (4-bromo-3-trifluoromethylphenyl) -2propenyl, group 3- (3-trifluoromethylphenyl) -2-propenyl, group 3- (4-trifluoromethylphenyl) -2propenyl, group 3- (2-trifluoromethoxyphenyl) -2-propenyl, group 3- (3-trifluoromethoxyphenyl) -

2-propenyl, group 3- (4-trifluoromethoxyphenyl) -2-propenyl, group 3- (2-methoxyphenyl) -2propenyl, group 3- (3-methoxyphenyl) -2-propenyl, group 3- (4-methoxyphenyl) - 2-propenyl, group 3- (3,4-dimethoxyphenyl) -2-propenyl, group 4- (4-chlorophenyl) -2-butenyl, group 4- (4-chlorophenyl) -3-butenyl, group 5- (4-chlorophenyl ) -2-pentenyl, group 5- (4-chlorophenyl) -4pentenyl, group 5- (4-chlorophenyl) -3-pentenyl, group 6- (4-chlorophenyl) -5-hexenyl, group 6- (4-chlorophenyl ) -4-hexenyl, group 6- (4-chlorophenyl) -3-hexenyl, group 6- (4-chlorophenyl) -3hexenyl or the like.

[0231] Examples of a C1-6 alkyl group (the alkyl group can be replaced by a morpholino group, benzoyl group and carbamoyl group that can have a C1-6 alkyl group as a substituent or cyano group) include a methyl group, group ethyl, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, morpholinomethyl group, 2-morpholinoethyl group, 3-morpholinopropyl group, 4morpholinobutyl group, 5-morpholinopentyl group, 6-morpholinoexyl group, benzoylmethyl group , 2-benzoylethyl group, 1-benzoylethyl group, 3-benzoylpropyl group, 4-benzoylbutyl group, 5-benzoylpentyl group, 6-benzoylhexyl group, carbamoylmethyl group, 2-carbamoyl group, 3-carbamoyl propyl group, 3-carbamoylpropyl group, 4carbamoylbutyl group, 5-carbamoylpentyl group, 6-carbamoylexyl group, 2-methyl-3carbamoylpropyl group, 1,1-dimethyl-2-carbamoyl group, methylcarbamoylmethyl group, 2-methylcarbamoyl propyl group, 3-methylcarbamoyl propyl group, 4-methylcarbamoylbutyl group, 5-methyl group bamoylpentyl, 6-methylcarbamoylexyl group, dimethylcarbamoylmethyl group, 2-dimethylcarbamoylethyl group, group 3 Petition 870190039560, from 26/04/2019, p. 153/876

145/854 dimethylcarbamoylpropyl, 4-dimethylcarbamoylbutyl group, 5dimethylcarbamoylpentyl group, 6-dimethylcarbamoylexyl group, diethylcarbamoylmethyl group, 2-diethylcarbamoyl group, 3-diethylcarbamoylpropyl group, diethylcarbyl group, 5diethylcarbyl group, 5diethylcarbyl group 2-n-propylcarbamoyl group, 3-npropylcarbamoyl group, 4-n-propylcarbamoyl group, 5-npropylcarbamoyl group, 6-n-propylcarbamoyl group, n-butylcarbamoyl group, 2-n-butylcarbamoyl group, 3-group 4-nbutilcarbamoyl butyl, 5-n-butylcarbamoyl group, 6-n-butylcarbamoyl group, n-hexylcarbamoyl group, 2-n-hexylcarbamoyl group, 3-nhexylcarbamoyl group, group 4-n-hexylcarbamoyl group, 5-group n-hexylcarbamoylexyl, cyanomethyl group, 2-cyanoethyl group, 1-cyanoethyl group, 3-cyanopropyl group, 4-cyanobutyl group, 5cianopenti group la, 6-cyanohexyl group or the like.

[0232] Examples of a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, cyano group, phenyl group, nitro group, C1-6 alkylthio group 6, C1-6 alkylsulfonyl group, C1-6 alkoxy phenyl group, C2-6 alkanoyloxy group, halogen substituted or substituted C1-6 alkyl group, C1-6 alkoxy group unsubstituted or substituted by halogen and group 1,2, 3-thiadiazolyl) include a C16 phenyl alkyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, a cyano group, a phenyl group, nitro group, C1-6 alkylthio group, C1-6 alkylsulfonyl group, phenyl C1-6 alkoxy group, C2-6 alkanoyloxy group, C1-6 alkyl group unsubstituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen and group

1,2,3-thiadiazolyl), for example, a benzyl group, group 1-phenethyl, group 2-phenethyl, group 3-phenylpropyl, group 2-phenylpropyl, group 4-phenylbutyl, group 5-phenylpentyl, group 4-phenylpentyl , 6-phenylexyl group, 4-biphenylylmethyl group, 2- (4-biphenylyl) ethyl group, 3- (4-biphenylyl) propyl group, 2- (4-biphenylyl) propyl group, 4- (4-biphenylyl) butyl group group

5- (4-biphenylyl) pentyl, group 4- (4-biphenylyl) pentyl, group 6- (4-biphenylyl) hexyl, group 2

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146/854 fluorobenzyl, group 3-fluorobenzyl, group 4-fluorobenzyl, group 2-chlorobenzyl, group 3-chlorobenzyl, group 4-chlorobenzyl, group 2-bromobenzyl, group 3bromobenzyl, group 4-bromobenzyl, group 2-iodobenzyl, group 2-iodobenzyl -iodobenzyl, group

4-iodobenzyl, group 2,3-difluorobenzyl, group 3,4-difluorobenzyl, group 3,5difluorobenzyl, group 2,4-difluorobenzyl, group 2,6-difluorobenzyl, group 2,4,6trifluorobenzyl, group 3,4,5 -trifluorobenzyl, group 2,3-dichlorobenzyl, group 3,4dichlorobenzyl, group 3,5-dichlorobenzyl, group 2,4-dichlorobenzyl, group 2,6dichlorobenzyl, group 2,4,6-trichlorobenzyl, group 3,4,5- trichlorobenzyl, 2difluoromethylbenzyl group, 3-difluoromethylbenzyl group, 4-difluoromethylbenzyl group, 4-chloro-3-difluoromethylbenzyl group, 3-chloro-4-difluoromethylbenzyl group, 3-bromo-4-fluoro-methylbenzyl group , 2-fluoro-4bromobenzyl group, 4-chloro-3-fluorobenzyl group, 2,3,4-trichlorobenzyl group, 4isopropylbenzyl group, 4-n-butylbenzyl group, 4-methylbenzyl group, 2-methylbenzyl group, 3-methylbenzyl group , 2,4-dimethylbenzyl group, 2,3-dimethylbenzyl group, 2,6dimethylbenzyl group, 3,5-dimethylbenzyl group, 2,5-dimethylbenzyl group, 2,4,6trimethylbenzyl group, group 3,5-ditrifluoromethylbenzyl, group 4-isopropoxybenzyl, group 4-nbutoxybenzyl, group 4-methoxybenzyl, group 2-methoxybenzyl, group 3-methoxybenzyl, group 2,4-dimethoxybenzyl, group 2,3-dimethoxybenzyl, group 2,6 -dimetoxibenzyl, 3,5-dimethoxybenzyl group, 2,5-dimethoxybenzyl group, 2,4,6-trimethoxybenzyl group, 3,5-ditrifluoromethoxybenzyl group, 2,3,4,5,6-pentafluorobenzyl group, 2isopropoxybenzyl group, group 3-chloro-4-methoxybenzyl, group 2-chloro-4trifluoromethoxybenzyl, group 3-methyl-4-fluorobenzyl, group 4-bromo-3trifluoromethylbenzyl, group 2-trifluoromethylbenzyl, group 3-trifluoromethylbenzyl, group 4-trifluoromethylbenzyl -3-trifluorometilbenzila group, 3-fluoro-4trifluorometilbenzila group, 4-chloro-3-pentafluoroetilbenzila group, 3-chloro-4pentafluoroetilbenzila, 2-pentafluoroetilbenzila group, 3-pentafluoroetilbenzila, 4pentafluoroetilbenzila group, trifluorometoxibenzila, trifluorometoxibenzila, pentafluoroetoxibenzila group, group group group 2-trifluoromethoxybenzyl,

4-trifluoromethoxybenzyl, group

3-fluoro-4-trifluoromethoxybenzyl,

3-pentafluoroethoxybenzyl, group 34-fluoro-3group group

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147/854

pentafluoroethoxybenzyl, group 3-chloro-4-trifluoromethoxybenzyl, 3-chloro-4- pentafluoroethoxybenzyl, group 2- (2-trifluoromethylphenyl) ethyl, group 2- (3- trifluoromethylphenyl) ethyl, group 2- (4-trifluoromethylphenyl) ethyl, group 2- (2- trifluoromethoxyphenyl) ethyl, group 2- (3-trifluoromethoxyphenyl) ethyl, group 2- (3- trifluoromethoxyphenyl) ethyl, group 2- (2-pentafluoroethoxyphenyl) ethyl, group 2- (3- pentafluoroethoxyphenyl) ethyl, group 2- (4-pentafluoroethoxyphenyl) ethyl, group 3- (2- trifluoromethylphenyl) propyl, group 3- (3-trifluoromethylphenyl) propyl, group 3- (4- trifluoromethylphenyl) propyl, group 3- (2-trifluoromethoxyphenyl) propyl, group 3- (3- trifluoromethoxyphenyl) propyl, group 3- (4-trifluoromethoxyphenyl) propyl, group 3- (3- pentafluoroethoxyphenyl) propyl, group 3- (4-pentafluoroethoxyphenyl) propyl, group 4- (3- pentafluoroethoxyphenyl) butyl, group 5- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethoxyphenyl) pentyl, group 6- (3- trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethylphenyl) hexyl, group 6- (4-

trifluoromethoxyphenyl) hexyl, 2-methylthiobenzyl group, 3-methylthiobenzyl group, 4methylthiobenzyl group, 2,3-dimethylthiobenzyl group, 2,4,6-trimethylthiobenzyl group, 2- (2-methylthiophenyl) ethyl group, 2- (3-methylthiophenyl) group , group 2- (4-methylthiophenyl) ethyl, group 3- (4-methylthiophenyl) propyl, group 4- (4-methylthiophenyl) butyl, group 5- (4-methylthiophenyl) pentyl, group 6- (4-methylthiophenyl) hexyl, group 6- 2-benzyloxybenzyl, group 3-benzyloxybenzyl, group 4-benzyloxybenzyl, group 2- (2-benzyloxyphenyl) ethyl, group 2- (3-benzyloxyphenyl) ethyl, group 2- (4-benzyloxyphenyl) ethyl, group 3- (4- benzyloxyphenyl) propyl, group 4- (4benzyloxyphenyl) butyl, group 5- (4-benzyloxyphenyl) pentyl, group 6- (4-benzyloxyphenyl) hexyl, group 2- (2-phenyloxy) benzyl, group 3- (2-phenyloxy) benzyl, group 4- (2-phenylethoxy) benzyl, group 2- (2- (2-phenylethoxy) phenyl) ethyl, group 2- (3- (2-phenylethoxy) phenyl) ethyl, group 2- (4- (2-phenylethoxy) ) phenyl) ethyl, group 3- (4- (2-phenylethoxy) phenyl) propyl, group 4- (4- (2-phenylethoxy) phenyl) butyl, gr upo 5- (4- (2-phenylethoxy) phenyl) pentyl, group 6- (4- (2-phenyloxy) phenyl) hexyl, group 2- (3-phenylpropoxy) benzyl, group 3- (3-phenylpropoxy) benzyl, group 4 - (3-phenylpropoxy) benzyl, group 2- (4-phenylbutoxy) benzyl, group 3- (4-phenylbutoxy) benzyl, group 4- (4-phenylbutoxy) benzyl, 2-acetyloxybenzyl, group 3acetyloxybenzyl, group 4-acetyloxybenzyl, group 2 - (2-acetyloxyphenyl) ethyl, group 2- (3-acetyloxyphenyl) ethyl, group 2- (4-acetyloxyphenyl) ethyl, group 3- (4-acetyloxyphenyl) propyl, group

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148/854

4- (4-acetyloxyphenyl) butyl, 5- (4-acetyloxyphenyl) pentyl group, 6- (4acetyloxyphenyl) hexyl group, 2-methanesulfonylbenzyl group, 3-methanesulfonylbenzyl group, 4-methanesulfonylbenzyl group, 3,4-dimethanesulfonyl group 3,4,5trimethanesulfonylbenzyl, group 2- (2-methanesulfonylphenyl) ethyl, group 2- (3-methanesulfonylphenyl) ethyl, group 2- (4-methanesulfonylphenyl) ethyl, group 3- (4-methanesulfonylphenyl) propyl, group 4- (4-methanesulfonyl) phenyl butyl, group 5- (4-methanesulfonylphenyl) pentyl, group 6- (4-methanesulfonylphenyl) hexyl, 2-cyanobenzyl group, 3-cyanobenzyl group, 4-cyanobenzyl group, 2,4-dicianobenzyl group, 3,4,5-tricianobenzyl group, group 2- (2-cyanophenyl) ethyl, group 2- (3-cyanophenyl) ethyl, group 2- (4-cyanophenyl) ethyl, group 3- (4-cyanophenyl) propyl, group 4- (4-cyanophenyl) butyl, group 5- (4-cyanophenyl) pentyl, group 6- (4-cyanophenyl) hexyl, group 2-nitrobenzyl, group

3-nitrobenzyl, 4-nitrobenzyl group, 2,6-dinitrobenzyl group, 3,4,5trinitrobenzyl group, 2- (2-nitrophenyl) ethyl group, 2- (3-nitrophenyl) ethyl group, 2- (4nitrophenyl) ethyl group , group 3- (4-nitrophenyl) propyl, group 4- (4-nitrophenyl) butyl, group 5- (4 nitrophenyl) pentyl, group 6- (4-nitrophenyl) hexyl, group 2- (1,2,3- thiadiazol-4-yl) benzyl, group 3- (1,2,3-thiadiazol-4-yl) benzyl, group 4- (1,2,3-thiadiazol-4-yl) benzyl or the like. [0233] Examples of a C2-6 alkenyl group include a vinyl group, 2propenyl group, 3-butenyl group, 2-butenyl group, 4-pentenyl group, 3-pentenyl group, 5-hexenyl group, 4-hexenyl group, group 3-hexenyl or similar.

[0234] A phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, cyano group, unsubstituted or substituted C1-6 alkyl group or halogen and C1- alkoxy group 6 unsubstituted or substituted by halogen), include an unsubstituted or substituted phenyl group from 1 to 5, preferably from 1 to 3 substituents selected from a group consisting of a halogen atom, cyano group, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen, as defined above, examples of which include a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, group

4-fluorophenyl, group 2-chlorophenyl, group 3-chlorophenyl, group 4-chlorophenyl, group 2bromophenyl, group 3-bromophenyl, group 4-bromophenyl, group 2-iodophenyl, group 3

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149/854 iodophenyl, 4-iodophenyl group, 2,3-difluorophenyl group, 3,4-difluorophenyl group, group

3.5- difluorophenyl, group 2,4-difluorophenyl, group 2,3,4,5,6-pentafluorophenyl, group

2.6- difluorophenyl, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2,4-dichlorophenyl group, group2,6-dichlorophenyl, group 3,4,5-trifluorophenyl, group 3,4, 5-trichlorophenyl, 2,4,6-trifluorophenyl group, 2,4,6-trichlorophenyl group, 2methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methyl-3-chlorophenyl group, 3-methyl-4 group -chlorophenyl, 2-chloro-4-methylphenyl group, 2-methyl-3-fluorophenyl group, 2trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2pentafluoroethylphenyl group, 3-pentafluoroethyl group, 4-pentafluoroethyl group

2- isopropylphenyl, 3-isopropylphenyl group, 4-isopropylphenyl group, 2-ter-butylphenyl group, 3-ter-butylphenyl group, 4-ter-butylphenyl group, 2-sec-butylphenyl group, 3-secbutilphenyl group, group 4- sec-butylphenyl, group 2-n-heptafluoropropylphenyl, group 3-nheptafluoropropylphenyl, group 4-n-heptafluoropropylphenyl, group 4-pentylphenyl, group 4hexylphenyl, group 2-methoxyphenyl, group 3-methoxyphenyl, group 3-methoxyphenyl, group 4-group 3-methoxyphenyl -methoxyphenyl, 2-fluoro-3-methoxyphenyl group, 2-fluoro-4-methoxyphenyl group, 2,6-dimethoxyphenyl group, 2,3,4-trifluorophenyl group, 2-fluoro-4-bromophenyl group, 4-chloro group -3-fluorophenyl, 2,3,4-trichlorophenyl group, 4-n-butylphenyl group, 2,4-dimethylphenyl group, 2,3-dimethylphenyl group, 2,6-dimethylphenyl group, 3,5-dimethylphenyl group, group 2, 5-dimethylphenyl, 2,4,6-trimethylphenyl group, 2,4,6-trimethoxyphenyl group, group

3,5-ditrifluoromethylphenyl, group 4-n-butoxyphenyl, group 2,4-dimethoxyphenyl, group 2,3dimethoxyphenyl, group 3,5-dimethoxyphenyl, group 2,5-dimethoxyphenyl, group 3,5ditrifluoromethoxyphenyl, group 3-chloro-4 -methoxyphenyl, 2-chloro-4trifluoromethoxyphenyl group, 3-methyl-4-fluorophenyl group, 4-bromo-3-trifluoromethylphenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2trifluoromethoxyphenyl group, 3-group , group 4-trifluoromethoxyphenyl, group

3-fluoro-2-trifluoromethoxyphenyl, 2-fluoro-3-trifluoromethoxyphenyl group, 3-fluoro-4trifluoromethoxyphenyl group, 3-chloro-2-trifluoromethoxyphenyl group, 2-chloro-3trifluoromethoxyphenyl group, 3-chloro-4-trifluoromethoxy group 2pentafluoroethoxyphenyl, 3-pentafluoroethoxyphenyl group, 4-pentafluoroethoxyphenyl group, 3-chloro-2-pentafluoroethoxyphenyl group, 2-chloro-3-pentafluoroethoxyphenyl group, group 3

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150/854 chloro-4-pentafluoroethoxyphenyl, 2-isopropoxyphenyl group, 3-isopropoxyphenyl group, 4-isopropoxyphenyl group, 2-ter-butoxyphenyl group, 3-ter-butoxyphenyl group, 4-terbutoxyphenyl group, 2-sec-butoxyphenyl group, 3-sec-butoxyphenyl group, 4-secbutoxyphenyl group, 2-n-heptafluoropropoxyphenyl group, 3-n-heptafluoropropoxyphenyl group, 4-n-pentoxiphenyl group, 4-n-hexyloxyphen group or similar.

[0235] A C2-6 phenyl alkanoyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1 alkoxy group -6 unsubstituted or substituted by halogen) includes a C2-6 phenyl alkanoyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), for example, a phenylacetyl group, 3-phenylpropionyl group, 4-phenylbutyryl group, 5-phenylpentanoyl group, 6-phenylexanoyl group, group 4-fluorophenylacetyl, group 3- (4-fluorophenyl) propionyl, group 4- (4-fluorophenyl) butyryl, group 5- (4-fluorophenyl) pentanoyl, group 6- (4-fluorophenyl) hexanoyl, group 2-chlorophenylacetyl, group 2 , 3,4,5,6-pentafluorophenylacet ila, group 3- (2-chlorophenyl) propionyl, group 4- (2-chlorophenyl) butyryl, group 5- (2-chlorophenyl) pentanoyl, group 6- (2-chlorophenyl) hexanoyl, group 3-chlorophenylacetyl, group 3- (3-chlorophenyl) ) propionyl, group 4- (3-chlorophenyl) butyryl, group 5- (3-chlorophenyl) pentanoyl, group 6- (3-chlorophenyl) hexanoyl, group 4-chlorophenylacetyl, group 3- (4chlorophenyl) propionyl, group 4- ( 4-chlorophenyl) butyryl, group 5- (4-chlorophenyl) pentanoyl, group 6- (4-chlorophenyl) hexanoyl, group 3,4-dichlorophenylacetyl, group 3- (3,4dichlorophenyl) propionyl, group 4- (3,4 -dichlorophenyl) butyryl, group 5- (3,4dichlorophenyl) pentanoyl, group 6- (3,4-dichlorophenyl) hexanoyl, group 2-methylphenylacetyl, group 3-methylphenylacetyl, group 4-methylphenylacetyl, group (2,4,6- trimethylphenyl) acetyl, group (2,6-dimethoxyphenyl) acetyl, group (2,4,5-trimethoxyphenyl) acetyl, group (3,5ditrifluoromethylphenyl) acetyl, group (3,5-ditrifluoromethoxyphenyl) acetyl, group 2trifluoromethylphenylacetyl, group 3- trifluoromethylphenylacetyl, group 4 870190039560, of 26/04/2019, p. 159/876

151/854 trifluoromethylphenylacetyl, group 2-phenylpropionyl, group 3- (2-methylphenyl) propionyl, group 3- (3-methylphenyl) propionyl, group 3- (4-methylphenyl) propionyl, group 3- (2trifluoromethylphenyl) propionyl, group 3 - (3-trifluoromethylphenyl) propionyl, group 3- (4trifluoromethylphenyl) propionyl, group 3- (3,5-dimethylphenyl) propionyl, group4- (4trifluoromethylphenyl) butyryl, group 5- (4-trifluoromethylphenyl) pentanoyl, group 6- (4 hexanoyl, group 4- (4-pentafluoroethylphenyl) butyryl, group5- (4 pentafluoroethylphenyl) pentanoyl, group 6- (4-pentafluoroethylphenyl) hexanoyl, group 2methoxyphenylacetyl, group 3-methoxyphenylacetyl, group 4-methoxyphenylmethyl, 3-methoxymethyl, group 4-methoxy , group 4trifluoromethoxyphenylacetyl, group 3- (2-methoxyphenyl) propionyl, group 3- (3methoxyphenyl) propionyl, group 3- (4-methoxyphenyl) propionyl, group 3- (2trifluoromethoxyphenyl) propionyl, group 3- (3-trifluoromethoxyphenyl) propionyl, group 3- (4trifluoromethoxyphenyl) prop ionyl, group 3- (3,5-dimethoxyphenyl) propionyl, group 4- (4-trifluoromethoxyphenyl) butyryl, group 5- (4-trifluoromethoxyphenyl) pentanoyl, group 6- (4-trifluoromethoxyphenyl) hexanoyl, group 4- (4-trifluoromethoxyphenyl) butyryl, group 5- (4pentafluoroethoxyphenyl) pentanoyl, group 6- (4-pentafluoroethoxyphenyl) hexanoyl or the like.

[0236] A C1-20 alkoxycarbonyl group (which can be substituted in the alkoxy group by at least one group selected from a group consisting of a halogen atom, an amino group which can have a C1-6 alkyl group as a substituent and group C1-6 alkoxy substituted by the C1-6 alkoxy group) is a group containing an alkoxy group having from 1 to 20 carbon atoms that can have from 1 to 7 groups selected from a group consisting of a halogen atom, an amino group that may have the C1-6 alkyl group and the C1-6 alkoxy group substituted by the C1-6 alkoxy group as a substituent and a carbonyl group, examples of which include a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl group , n-pentyloxycarbonyl group, n-hexyloxycarbonyl group, n-heptyloxycarbonyl group, n-octyloxycarbonyl group, n-nonyloxycarbonyl group, ndecyloxycarbonyl group, n-undecyloxycarbonyl group, n-dodecyloxycarbonyl group, n group tridecyloxycarbonyl, n-tetradecyloxycarbonyl group, n-pentadecyloxycarbonyl group,

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152/854 n-hexadecyloxycarbonyl group, n-heptadecyloxycarbonyl group, noctadecyloxycarbonyl group, n-nonadecyloxycarbonyl group, n-icosyloxycarbonyl group, chloromethoxycarbonyl group, trichloromethoxycarbonyl group, 2-bromoethoxycarbonyl group, 3-bromooxycarbonyl group 4iodobutoxycarbonyl, group 5,5,5,4,4,3,3-heptafluoropentyloxycarbonyl, group 4,4,4,3,3,2,2-heptafluorobutoxycarbonyl, group 5-chloropentyloxycarbonyl, group 6bromohexyloxycarbonyl, group 7-chloroeptyloxycarbonyl, group 8-iodooctyloxycarbonyl,

group 9-chlorononyloxycarbonyl, group 10-bromodecyloxycarbonyl, group 11- fluoroundecyloxycarbonyl, group 12-iodododecyloxycarbonyl, group 12- chlorododecyloxycarbonyl, group 13-fluorotridecyloxycarbonyl, group 14- bromotetradecyloxycarbonyl, group 15-iodopentadecyloxycarbonyl, group 16- chlorohexadecyloxycarbonyl, group 17-bromoeptadecyloxycarbonyl, group 18- fluorooctadecyloxycarbonyl, group 19-chlorononadecyloxy carbonyl, group 20- chloroicosyloxycarbonyl, group aminomethoxycarbonyl, group diethylaminomethoxycarbonyl, group 2-diethylaminoethoxycarbonyl, group 3- diethylaminopropoxycarbonyl, group 4-diethylaminobutoxycarbonyl, group 5- diethylaminopentyloxycarbonyl, group 6-diethylaminoexyloxycarbonyl, group 7- diethylaminoeptyloxycarbonyl, group 8-diethylaminooctyloxycarbonyl, group 9- diethylaminononyloxycarbonyl, group 10-diethylaminodecyloxycarbonyl, group 11- diethylaminoundecyloxycarbonyl, group 12-diethylaminododecyloxycarbonyl, group 13- diethylaminotridecyloxycarbonyl, group 14-diethylaminotetradecyloxycarbonyl, group 15-

diethylaminopentadecyloxycarbonyl, group 16-diethylaminoexadecyloxycarbonyl, group 17-diethylaminoeptadecyloxycarbonyl, group 18-diethylaminooctadecyloxycarbonyl, group 19-diethylaminononadecyloxycarbonyl, 2-group, 2-diethylaminoxyoxycarbonyl, 2-group - (2-butoxyethoxy) ethoxycarbonyl, group 2- (2pentyloxyethoxy) ethoxycarbonyl, group 2- (2-hexyloxyethoxy) ethoxycarbonyl, group 2methoxyethoxyethoxycarbonyl, group 3- (3-methoxypropoxy) propoxycarbonyl, group 4- (4methoxyxyoxy) butoxycarbonyl group (5-methoxypentyloxy) pentyloxycarbonyl, group 6 (6-methoxyoxyoxy) hexyloxycarbonyl, group 7- (2-methoxyethoxy) heptyloxycarbonyl, group 8Petition 870190039560, from 26/04/2019, p. 161/876

153/854 (1-methoxyethoxy) octyloxycarbonyl, group 9- (1-methoxyethoxy) nonyloxycarbonyl, group 10 (2-methoxyethoxy) decyloxycarbonyl, group 11- (2-methoxyethoxy) undecyloxycarbonyl, group 12- (2-methoxyethoxy) dodecyloxycarbonyl group 12- (1-methoxyethoxy) dodecyloxycarbonyl, group 13- (2-methoxyethoxy) tridecyloxycarbonyl, group 14- (1methoxyethoxy) tetradecyloxycarbonyl, group 15- (2-methoxyethoxy) pentadecyloxycarbonyl, group 16- (1-methoxy-ethyloxyoxycarbonyl) group (2methoxyethoxy) heptadecyloxycarbonyl, group 18- (1-methoxyethoxy) octadecyloxycarbonyl, group 19- (2-methoxyethoxy) nonadecyloxycarbonyl, group 20- (1methoxyethoxy) icosyloxycarbonyl, dimethylaminomethoxycarbonyl group, 3-methylmethylamino group ) propoxycarbonyl, group 4propylaminobutoxycarbonyl, group 5-hexylaminopentyloxycarbonyl, group 6pentylaminohexyloxycarbonyl, group 7- (N-ethyl-N-propylamino) heptyloxycarbonyl, group 8 (N-propyl-N-hexyl) aminooctyloxycarbonyl, group 9- (N-methyl-N-pentyl) amino) nonyloxycarbonyl, group 10-dipropylaminodecyloxycarbonyl, group 11dipentylaminoundecyloxycarbonyl, group 12-diexylaminododecyloxycarbonyl, group 12dibutylaminododecyloxycarbonyl, group 13- (N-ethyl-N-butylamino) tridecyloxycarbonyl, hexyl-methylcarbonyl, group-14 , 16-dimethylaminoexadecyloxycarbonyl, group 17dimethylaminoeptadecyloxycarbonyl, group 18-dimethylaminooctadecyloxycarbonyl, group 19-dimethylaminononadecyloxycarbonyl, group 20-dimethylaminoicosyloxycarbonyl or similar.

[0237] Examples of a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen, group C1-6 alkoxy unsubstituted or substituted by halogen, nitro group, C1-6 alkylthio group unsubstituted or substituted by halogen, amino group which may have a C1-6 alkanoyl group, C1-6 alkoxy phenyl group, C1-6 alkoxycarbonyl group and 1,2,3-thiadiazolyl group) include a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom , C1-6 alkyl group does not

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154/854 substituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen, nitro group, C1-6 alkylthio group unsubstituted or substituted by halogen, amino group that may have 1 to 2 alkanoyl groups, phenyl group C1-6 alkoxy, C1-6 alkoxycarbonyl group and 1,2,3-thiadiazolyl group), for example, a benzyloxycarbonyl group, 1-phenethyloxycarbonyl group, 2-phenethyloxycarbonyl group, 3-phenylpropoxycarbonyl group, 2-phenylpropoxycarbonyl group, 4-phenylbutoxycarbonyl group , 5-phenylpentyloxycarbonyl group, 4-phenylpentyloxycarbonyl group,

6-phenylexyloxycarbonyl group, 2-fluorobenzyloxycarbonyl group, group 3- fluorobenzyloxycarbonyl, group 4-fluorobenzyloxycarbonyl, group 2- chlorobenzyloxycarbonyl, group 3-chlorobenzyloxycarbonyl, group 4- chlorobenzyloxycarbonyl, group 2-bromobenzyloxycarbonyl, group 3- bromobenzyloxycarbonyl, group 4-bromobenzyloxycarbonyl, group 2- iodobenzyloxycarbonyl, group 3-iodobenzyloxycarbonyl, group 4- iodobenzyloxycarbonyl, group 2,3-difluorobenzyloxycarbonyl, group 3.4- difluorobenzyloxycarbonyl, group 3,5-difluorobenzyloxycarbonyl, group 2.4- difluorobenzyloxycarbonyl, group 2,6-difluorobenzyloxycarbonyl, group 2.4.6- trifluorobenzyloxycarbonyl, group 3,4,5-trifluorobenzyloxycarbonyl, group 2.3- dichlorobenzyloxycarbonyl, group 3,4-dichlorobenzyloxycarbonyl, group 3.5- dichlorobenzyloxycarbonyl, group 2,4-dichlorobenzyloxycarbonyl, group 2.6- dichlorobenzyloxycarbonyl, group 2,4,6-trichlorobenzyloxycarbonyl, 3.4.5- trichlorobenzyloxycarbonyl, group 2,3,4,5,6-pentafluorobenzyloxycarbonyl, group 2-

difluoromethylbenzyloxycarbonyl, group 3-difluoromethylbenzyloxycarbonyl, group 4difluoromethylbenzyloxycarbonyl, group 4-chloro-3-difluoromethylbenzyloxycarbonyl, group

3-chloro-4-difluoromethylbenzyloxycarbonyl, group 3-bromo-4-difluoromethylbenzyloxycarbonyl, group 3,5-difluoro-4-difluoromethylbenzyloxycarbonyl, group 2-trifluoromethylbenzyloxycarbonyl, group 2-fluoro-4-bromobenzyloxycarbonyl, group 3 , 2,3,4-trichlorobenzyloxycarbonyl group, group

4- isopropylbenzyloxycarbonyl, group 4-n-butylbenzyloxycarbonyl, group 4methylbenzyloxycarbonyl, group 2-methylbenzyloxycarbonyl, group 3methylbenzyloxycarbonyl, group 2,4-dimethylbenzyloxycarbonyl, group 2,3-

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155/854 dimethylbenzyloxycarbonyl, group

2,6-dimethylbenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl group, 2,5-dimethylbenzyloxycarbonyl group, 2,4,6trimethylbenzyloxycarbonyl group, 3,5-ditrifluoromethylbenzyloxycarbonyl group, 4isopropoxybenzyloxycarbonyl group, 4-n-butoxybenzyl group, 4-n-butoxybenzyl group methoxybenzyloxycarbonyl, 3methoxybenzyloxycarbonyl group, 2,4-dimethoxybenzyloxycarbonyl group, 2,3dimethoxybenzyloxycarbonyl group, 2,6-dimethoxybenzyloxycarbonyl group, 3,5dimethoxybenzyloxycarbonyl group, 2,5-dimethoxybenzyloxycarbonyl group, 2,4,6trimethoxybenzyl group group 2 isopropoxybenzyloxycarbonyl, group 3-chloro-4-methoxybenzyloxycarbonyl, group 2-chloro4-fluoromethoxybenzyloxycarbonyl, group 3-methyl-4-fluorobenzyloxycarbonyl, group 4bromo-3-trifluoromethylbenzyloxycarbonyl, group 4-trifluoromethylmethyl-4-trifluoromethyl -3trifluoromethylbenzyloxycarbonyl, group 3-f luoro-4-trifluoromethylbenzyloxycarbonyl, group

2-pentafluoroetilbenziloxicarbonila group, 4-chloro-3-pentafluoroetilbenziloxicarbonila group, 3-chloro-4-pentafluoroetilbenziloxicarbonila, pentafluoroetilbenziloxicarbonila 3-, 4-pentafluoroetilbenziloxicarbonila group, 2trifluorometoxibenziloxicarbonila group, 3-trifluorometoxibenziloxicarbonila group, 4trifluorometoxibenziloxicarbonila group, 4-fluoro-3- trifluorometoxibenziloxicarbonila group, 3-fluoro-4trifluorometoxibenziloxicarbonila, 2pentafluoroetoxibenziloxicarbonila group, 3-pentafluoroetoxibenziloxicarbonila group, 4-pentafluoroetoxibenziloxicarbonila group, 3-chloro-4trifluorometoxibenziloxicarbonila group, 3-chloro-4-pentafluoroetoxibenziloxicarbonila group, 2- (2-trifluoromethylphenyl) etoxicarbonila, group 2- (3trifluoromethylphenyl) ethoxycarbonyl, group 2- (4-trifluoromethylphenyl) ethoxycarbonyl, group (2trifluoromethoxyphenyl) methoxycarbonyl, group (3-trifluoromethoxyphenyl) methoxycarbonyl, group 2- (4-trifluoromethoxyphenylphenylphenylphenylphenyl), group 2- il) ethoxycarbonyl, group 2- (3-pentafluoroethoxyphenyl) ethoxycarbonyl, group 2- (4-pentafluoroethoxyphenyl) ethoxycarbonyl, group 3- (2trifluoromethylphenyl) propoxycarbonyl, group 3- (3-trifluoromethylphenyl) propoxycarbonyl,

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156/854 group 3- (4-trifluoromethylphenyl) propoxycarbonyl, group 3- (2-trifluoromethoxyphenyl) propoxycarbonyl, group 3- (4-trifluoromethoxyphenyl) propoxycarbonyl, 3- (3-trifluoromethoxyphenyl) propoxycarbonyl, 3- (3pentafluoro) 4pentafluoroethoxyphenyl) propoxycarbonyl, group4- (3pentafluoroethoxyphenyl) butoxycarbonyl, group 5- (4-trifluoromethylphenyl) pentyloxycarbonyl, group 4- (4-trifluoromethylphenyl) pentyloxycarbonyl, group4- (4trifluoromethylcarbonyl), 6-group - (4-trifluoromethylphenyl) hexyloxycarbonyl, group6- (4trifluoromethoxyphenyl) hexyloxycarbonyl, group 2-methylthiobenzyloxycarbonyl, group 3methylthiobenzyloxycarbonyl, group 4-methylthiobenzyloxycarbonyl, group 2- (2methylthiylphenyl) -methyl (2) 4methylthiophenyl) ethoxycarbonyl, group 3- (4-methylthiophenyl) propoxycarbonyl, group 4- (4methylthiophenyl) butoxycarbonyl, group 5- (4-methylthiophenyl) pentyloxycarbonyl a, group 6- (4methylthiophenyl) hexyloxycarbonyl, group 2-trifluoromethylthiobenzyloxycarbonyl, group 3trifluoromethylthiobenzyloxycarbonyl, group 4-trifluoromethylthiobenzyloxycarbonyl, group 2 (2-trifluoromethylthiofilyl) 2- (3) ethoxycarbonyl, group 3- (4 trifluoromethylthiophenyl) propoxycarbonyl, group 4- (4-trifluoromethylthiophenyl) pentyloxycarbonyl, group 5- (4-trifluoromethylthiophenyl) group, group 6- (4-trifluoromethylthiophenyl), group 2 ((4-trifluoromethylthiophenyl) benzyloxycarbonyl, group 2 benzyloxybenzyloxycarbonyl, group 2- (2-benzyloxyphenyl) ethoxycarbonyl, group 2- (3-benzyloxyphenyl) ethoxycarbonyl, group 2- (4-benzyloxyphenyl) ethoxycarbonyl, group 3- (4-benzyloxyphenyl) propoxycarbonyl, group 4- (4benzyloxyphenyl) butyl group 4-benzyloxyphenyl) pentyloxycarbonyl, group 6- (4benzyloxyphenyl) hexyloxycarbonyl, group 2- (2-phenylethoxy) benzyloxycarbonyl, group 3- ( 2phenyloxy) benzyloxycarbonyl, group 4- (2-phenyloxy) benzyloxycarbonyl, group 2- [2- (2phenyloxy) phenyl] ethoxycarbonyl, group 2- [3- (2-phenylethoxy) phenyl] ethoxycarbonyl, group 2- [4 (2- phenylethoxy) phenyl] ethoxycarbonyl, group 3- (4- (2-phenylethoxyphenyl)) propoxycarbonyl, group 4- (4- (2-phenylethoxyphenyl)) butoxycarbonyl, group 5- (4- (2-phenylethoxyphenyl)) pentyloxycarbonyl,

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157/854 group 6- (4- (2-phenylethoxyphenyl)) hexyloxycarbonyl, group 2- (3-phenylpropoxy) benzyloxycarbonyl, group 3- (3-phenylpropoxy) benzyloxycarbonyl, group 4- (3-phenylpropoxy) benzyloxycarbonyl, group 2- (4-phenylbutoxy ) benzyloxycarbonyl, group 3- (4-phenylbutoxy) benzyloxycarbonyl, group 4- (4-phenylbutoxy) benzyloxycarbonyl, group 2metoxicarbonylbenzyloxycarbonyl, group 3-methoxycarbonylbenzyloxycarbonyl, group 4-methoxycarbonylbenzyloxycarbonyl, group 2- (2

2- (3-methoxycarbonylphenyl) ethoxycarbonyl, group 2- (4-methoxycarbonylphenyl) ethoxycarbonyl, group 3- (4-methoxycarbonylphenyl) propoxycarbonyl, group 4- (4methoxycarbonylphenyl) butoxycarbonyl, group 5- (4-methoxycarbonylphenyl) pentyloxycarbonyl (4-methoxycarbonylphenyl) hexyloxycarbonyl, group 2-butyrylaminobenzyloxycarbonyl, group 3-butyrylaminobenzyloxycarbonyl, group 4butyrylaminobenzyloxycarbonyl, group 2- (2-butyrylaminophenyl) ethoxycarbonyl, group 2- (3butyrylaminophenyl) to the group (2- - (4butyrylaminophenyl) propoxycarbonyl, group 4- (4-butyrylaminophenyl) butoxycarbonyl, group

5- (4-butyrylaminophenyl) pentyloxycarbonyl, group 6- (4-butyrylaminophenyl) hexyloxycarbonyl, group 2-nitrobenzyloxycarbonyl, group 3-nitrobenzyloxycarbonyl, group 4nitrobenzyloxycarbonyl, group 2- (2-nitrophenyl) ethoxycarbonyl, group 2- (3nn group 2- (2,4-dinitrophenyl) ethoxycarbonyl, group 2- (2,4,6-

trinitrophenyl) methoxycarbonyl, group 2- (4-nitrophenyl) ethoxycarbonyl, group 3- (4- nitrophenyl) propoxycarbonyl, group 4- (4-nitrophenyl) butoxycarbonyl, group 5- (4- nitrophenyl) pentyloxycarbonyl, group 6- (4-nitrophenyl) hexyloxycarbonyl, group 2- aminobenzyloxycarbonyl, group 3-aminobenzyloxycarbonyl, group 4- aminobenzyloxycarbonyl, group 2- (2-aminophenyl) ethoxycarbonyl, group 2- (3- aminophenyl) ethoxycarbonyl, group 2- (4-aminophenyl) ethoxycarbonyl, group 3- (4- aminophenyl) propoxycarbonyl, group 4- (4-aminophenyl) butoxycarbonyl, group 5- (4-

aminophenyl) pentyloxycarbonyl, group 6- (4-aminophenyl) hexyloxycarbonyl, group 2acetylaminobenzyloxycarbonyl, group 3-propionylaminobenzyloxycarbonyl, group 4pentanoylaminobenzyloxycarbonyl, group 2- (2-hexaneylaminophenyl) ethoxycarbonyl, group 2- (3-group) -acetylaminophenyl) ethoxycarbonyl, group 3- (4-acetylaminophenyl) propoxycarbonyl, group 4- (4Petition 870190039560, of 26/04/2019, page 166/876

158/854 acetylaminophenyl) butoxycarbonyl, group 5- (4-acetylaminophenyl) pentyloxycarbonyl, group

6- (4-acetylaminophenyl) hexyloxycarbonyl, group 2-ethoxycarbonylbenzyloxycarbonyl, group

3-ethoxycarbonylbenzyloxycarbonyl, group 4-ethoxycarbonylbenzyloxycarbonyl, group 2- (2-methoxycarbonylphenyl) ethoxycarbonyl, group 2- (3-butoxycarbonylphenyl) ethoxycarbonyl, group 2- (4-propoxycarbonylphenyl) ethoxycarbonyl, group 3- (4- (4-pentyloxycarbonylphenyl) butoxycarbonyl, group 5- (4-hexyloxycarbonylphenyl) pentyloxycarbonyl, group 6- (4ethoxycarbonylphenyl) hexyloxycarbonyl, group 2- (1,2,3-thiadiazol-4-yl) benzyloxycarbonyl, group 3- (1,2 , 3-thiadiazol-4-yl) benzyloxycarbonyl, group 4- (1,2,3-thiadiazol-4yl) benzyloxycarbonyl or the like.

[0238] A C3-6 phenyl alkenyloxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1 alkoxy group -6 unsubstituted or substituted by halogen) is a group containing 1 to 5 unsubstituted or substituted phenyl group, preferably 1 to 3 groups selected from a group consisting of a halogen atom, a C1 alkyl halogen group -6 and a C1-6 alkoxy group unsubstituted or substituted by halogen, an alkenyloxy group having 3 to 6 carbon atoms and 1 to 3 double bonds, and a carbonyl group. These groups can be found in the trans or cis form and both forms are of course included. For example, an unsubstituted 3-phenyl-2-propenyloxycarbonyl group (common name: cinnamyloxycarbonyl group), 4-phenyl-2-butenyloxycarbonyl group, 4-phenyl-3 butenyloxycarbonyl group, 5-phenyl-2-pentenyloxycarbonyl group , 5-phenyl-4pentenyloxycarbonyl group, 5-phenyl-3-pentenyloxycarbonyl group, 6-phenyl-5-hexenyloxycarbonyl group, 6-phenyl-4-hexenyloxycarbonyl group, 6-phenyl-3hexenyloxycarbonyl group, 4-phenyl-1,3-butadienyloxycarbonyl group , group 6-phenyl-1,3,5 hexatrienyloxycarbonyl, group 6-phenyl-3-hexenyloxycarbonyl, group 3- (2-fluorophenyl) -2propenyloxycarbonyl, group 3- (3-fluorophenyl) -2-propenyloxycarbonyl, group 3- ( 4fluorophenyl) -2-propenyloxycarbonyl, group 3- (2,3-difluorophenyl) -2-propenyloxycarbonyl, group 3- (2,4-difluorophenyl) -2-propenyloxycarbonyl, group 3- (3,4-difluorophenyl) -2

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159/854 propenyloxycarbonyl, group 3- (3,5-difluorophenyl) -2-propenyloxycarbonyl, group 3- (2-chlorophenyl) -2-propenyloxycarbonyl, group 3- (3-chlorophenyl) -2-propenyloxycarbonyl, group

3- (4-chlorophenyl) -2-propenyloxycarbonyl, group 3- (2,3-dichlorophenyl) -2-propenyloxycarbonyl, group 3- (2,4-dichlorophenyl) -2-propenyloxycarbonyl, group 3- (3,4dichlorophenyl) -2-propenyloxycarbonyl, group 3- (3,5-dichlorophenyl) -2-propenyloxycarbonyl, group 3- (2-bromophenyl) -2-propenyloxycarbonyl, group 3- (3-bromophenyl) -2propenyloxycarbonyl, group 3- (4- bromophenyl) -2-propenyloxycarbonyl, group 3- (2-fluoro-

4- bromophenyl) -2-propenyloxycarbonyl, group 3- (2,3,4,5,6-pentafluorophenyl) -2-propenyloxycarbonyl, group 3- (4-chloro-3-fluorophenyl) -2-propenyloxycarbonyl, group 3 ( 2,3,4-trichlorophenyl) -2-propenyloxycarbonyl, group 3- (2,4,6-trichlorophenyl) -2propenyloxycarbonyl, group 3- (4-isopropylphenyl) -2-propenyloxycarbonyl, group 3- (4-nbutylphenyl) - 2-propenyloxycarbonyl, group 3- (2,4-dimethylphenyl) -2-propenyloxycarbonyl, group 3- (2,3-dimethylphenyl) -2-propenyloxycarbonyl, group 3- (2,6-dimethylphenyl) -2propenyloxycarbonyl, group 3- (3,5-dimethylphenyl) -2-propenyloxycarbonyl, group 3- (2,5dimethylphenyl) -2-propenyloxycarbonyl, group 3- (2,4,6-trimethylphenyl) -2-propenyloxycarbonyl, group 3- (3,5- ditrifluoromethylphenyl) -2-propenyloxycarbonyl, group 3- (4-n-butoxyphenyl) -2propenyloxycarbonyl, group 3- (2,4-dimethoxyphenyl) -2-propenyloxycarbonyl, group 3- (2,3dimethoxyphenyl) -2-propenyloxycarbonyl, group 3 - (2,6-dimethoxyphenyl) -2propenyloxycarbonyl, group 3- (3,5-dimethoxyphenyl) -2-propenyloxycarbonyl, group 3- (2,5dime toxifenyl) -2-propenyloxycarbonyl, group 3- (3,5-ditrifluoromethoxyphenyl) -2propenyloxycarbonyl, group 3- (3-chloro-4-methoxyphenyl) -2-propenyloxycarbonyl, group 3 (2-chloro-4-trifluoromethoxyphenyl) -2 -propenyloxycarbonyl, group 3- (3-methyl-4-fluorophenyl) -2propenyloxycarbonyl, group 3- (4-bromo-3-trifluoromethylphenyl) -2-propenyloxycarbonyl, group 3- (2-methylphenyl) -2-propenyloxycarbonyl, group 3 - (3-methylphenyl) -2propenyloxycarbonyl, group 3- (4-methylphenyl) -2-propenyloxycarbonyl, group 3- (2trifluoromethylphenyl) -2-propenyloxycarbonyl, group 3- (3-trifluoromethylphenyl) -2propenyloxycarbonyl, group 3- (4- trifluoromethylphenyl) -2-propenyloxycarbonyl, 3- (2trifluoromethoxyphenyl) -2-propenyloxycarbonyl, group 3- (3-trifluoromethoxyphenyl) -2propenyloxycarbonyl, group 3- (4-trifluoromethoxyphenyl) -2-propenyloxycarbonyl, group 3 (2) -propenyloxycarbonyl, group 3- (3-methoxyphenyl) -2-propenyloxycarbonyl,

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160/854 group 3- (4-methoxyphenyl) -2-propenyloxycarbonyl, group 3- (3,4-dimethoxyphenyl) -2propenyloxycarbonyl, group 4- (4-chlorophenyl) -2-butenyloxycarbonyl, group 4- (4-chlorophenyl) -3 -butenyloxycarbonyl, group 5- (4-chlorophenyl) -2-pentenyloxycarbonyl, group 5 (4-chlorophenyl) -4-pentenyloxycarbonyl, group 5- (4-chlorophenyl) -3-pentenyloxycarbonyl, group 6- (4-chlorophenyl) - 5-hexenyloxycarbonyl, group 6- (4-chlorophenyl) -4hexenyloxycarbonyl, group 6- (4-chlorophenyl) -3-hexenyloxycarbonyl, group 6- (4chlorophenyl) -2-hexenyloxycarbonyl or the like.

[0239] A phenoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group, and unsubstituted C1-6 alkoxy group or substituted by halogen) includes, a phenoxycarbonyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, unsubstituted C1-6 alkyl group or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), for example, a phenoxycarbonyl group, 2-fluorophenoxycarbonyl group, 3-fluorophenoxycarbonyl group, 2,3,4,5,6pentafluorophenoxycarbonyl group, 4-fluorophenoxycarbonyl group, group 2chlorophenoxycarbonyl, 3-chlorophenoxycarbonyl group, 4-chlorophenoxycarbonyl group, 2,3-dichlorophenoxycarbonyl group, 3,4-dichlorophenoxycarbonyl group, 3,5dichlorophenoxycarbonyl group, group 2-b romophenoxycarbonyl, 3-bromophenoxycarbonyl group, 4-bromophenoxycarbonyl group, 2-methylphenoxycarbonyl group, 3methylphenoxycarbonyl group, 4-methylphenoxycarbonyl group, 2-ethylphenoxycarbonyl group, group

3- ethylphenoxycarbonyl, group 4-ethylphenoxycarbonyl, group 4-propylphenoxycarbonyl, group

4- tert-butylphenoxycarbonyl, dimethylphenoxycarbonyl, pentylphenoxycarbonyl, bromophenoxycarbonyl, trichlorophenoxycarbonyl, isopropylphenoxycarbonyl, dimethylphenoxycarbonyl, group group group group group 4-butylphenoxycarbonyl, group 2,3-

3.4.5- trimethylphenoxycarbonyl, group 4-

4-hexylphenoxycarbonyl, group 2-fluoro-44-chloro-3-fluorophenoxycarbonyl,

2.4.6- trichlorophenoxycarbonyl,

4-n-butylphenoxycarbonyl,

2.6- dimethylphenoxycarbonyl, group group

2,3,44group group group group

2.4-

3.5-

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161/854

dimethylphenoxycarbonyl, group 2,5-dimethylphenoxycarbonyl, group 2.4.6- trimethylphenoxycarbonyl, group 3,5-ditrifluoromethylphenoxycarbonyl, group 4-n- butoxyphenoxycarbonyl, group 2,4-dimethoxyphenoxycarbonyl, group 2.3- dimethoxyphenoxycarbonyl, group 2,6-dimethoxyphenoxycarbonyl, group 3.5- dimethoxyphenoxycarbonyl, group 2,5-dimethoxyphenoxycarbonyl, group 3.5-

ditrifluoromethoxyphenoxycarbonyl, group 3-chloro-4-methoxyphenoxycarbonyl, group 2-chloro-

4-tnfluorometoxifenoxicarbonila group, 3-methyl-4-fluorofenoxicarbonila group, 3trifluorometilfenoxicarbonila 4-bromo-2-trifluorometilfenoxicarbonila group, 3trifluorometilfenoxicarbonila, 4-trifluorometilfenoxicarbonila group, 2pentafluoroetilfenoxicarbonila, 3-pentafluoroetilfenoxicarbonila group, 4pentafluoroetilfenoxicarbonila, 2-metoxifenoxicarbonila group, 3methoxyphenoxycarbonyl, group 4-methoxyphenoxycarbonyl, group 2-ethoxyphenoxycarbonyl, group 3-ethoxyphenoxycarbonyl, group 4-ethoxyphenoxycarbonyl, group 4propoxyphenoxycarbonyl, group 4-ter-butoxyphenoxycarbonyl, group 4-nbutoxyphenoxycarbonyl, group 4-nbutoxyphenoxycarbonyl 4-hexyloxyphenoxycarbonyl, group 2trifluoromethoxyphenoxycarbonyl, group 3-tnfluoromethoxyphenoxycarbonyl, group 4trifluoromethoxyphenoxycarbonyl, group 2-pentafluoroethoxyphenoxycarbonyl, group 3 pentafluoroethoxyphenoxycarbonyl, group 4-pentafluoro [0240] A phenyl C1-6 alkylcarbamoyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and Ci alkoxy group -6 unsubstituted or substituted by halogen) includes a phenyl C1-6 alkylcarbamoyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), for example, a benzylcarbamoyl group, 2-phenethylcarbamoyl group, 3-phenylpropylcarbamoyl group, 2-phenylpropylcarbamoyl group, 4-phenylbutylcarbamoyl group, group 5-phenylpenticarbamoyl, group 4-phenylpentylcarbamoyl, group 6-phenylexylcarbamoyl, group 2Petition 870190039560, of 26/04/2019, p. 170/876

162/854

fluorobenzylcarbamoyl, group 3-fluorobenzylcarbamoyl, group 4- fluorobenzylcarbamoyl, group 2-chlorobenzylcarbamoyl, group 3- chlorobenzylcarbamoyl, group 4-chlorobenzylcarbamoyl, group 2- bromobenzylcarbamoyl, group 3-bromobenzylcarbamoyl, group 4- bromobenzylcarbamoyl, group 2-iodobenzylcarbamoyl, group 3- iodobenzylcarbamoyl, group 4-iodobenzylcarbamoyl, group N-benzyl-N- methylcarbamoyl group N-methyl -N- (2-phenethyl) carbamoyl, group N-methyl-N- (3-

phenylpropyl) carbamoyl, N-methyl-N- (2-phenylpropyl) carbamoyl group, N-methyl-N- (4phenylbutyl) carbamoyl group, N-methyl-N- (5-phenylpentyl) carbamoyl group, N-methyl-N group - (4-phenylpentyl) carbamoyl, group N-methyl-N- (6-phenylexyl) carbamoyl, group N- (2-fluorobenzyl) -N-methylcarbamoyl, group N- (3-fluorobenzyl) -N-methylcarbamoyl, group N (4-fluorobenzyl) ) -N-methylcarbamoyl, group N- (2-chlorobenzyl) -N-methylcarbamoyl, group N- (3-chlorobenzyl) -N-methylcarbamoyl, group N- (4-chlorobenzyl) -N-methylcarbamoyl, group N- (2 -bromobenzyl) -N-methylcarbamoyl, group N- (3-bromobenzyl) -Nmethylcarbamoyl, group N- (4-bromobenzyl) -N-methylcarbamoyl, group N, Ndibenzylcarbamoyl, group N-benzyl-N- (2-phenethyl) carbamoyl , N-benzyl- (3-phenylpropyl) carbamoyl group, N-benzyl-N- (2-phenylpropyl) carbamoyl group, N-benzyl-N (4-phenylbutyl) carbamoyl group, N-benzyl-N- (5-phenylpentyl) group carbamoyl, N-benzyl-N (4-phenylpentyl) group carbamoyl, N-benzyl-N- (6-phenylexyl) carbamoyl group, N-benzyl-N (2-fluorobenzi group l) carbamoyl, N-benzyl-N- (3-fluorobenzyl) carbamoyl group, Nbenzyl-N- (4-fluorobenzyl) carbamoyl group, N-benzyl-N- (2-chlorobenzyl) carbamoyl group, N-benzyl-N group - (3-chlorobenzyl) carbamoyl, N-benzyl-N- (4 chlorobenzyl) carbamoyl group, N-benzyl-N- (2-bromobenzyl) carbamoyl group, N-benzylN- (3-bromobenzyl) carbamoyl group, group 2, 3-difluorobenzylcarbamoyl, difluorobenzylcarbamoyl group, difluorobenzylcarbamoyl, dichlorobenzylcarbamoyl, dichlorobenzylcarbamoyl, bromobenzylcarbamoyl, group group group group group group group

N-benzyl-N- (4-bromobenzyl) carbamoyl,

3,4-difluorobenzylcarbamoyl,

2.4- difluorobenzylcarbamoyl,

2,3-dichlorobenzylcarbamoyl,

3.5- dichlorobenzylcarbamoyl,

2,6-dichlorobenzylcarbamoyl, group 2-fluoro-44-chloro-3-fluorobenzylcarbamoyl, group 2,3,4group group group group group

3.5-

2.6-

3.4-

2.4-

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163/854 trichlorobenzylcarbamoyl, group 3,4,5-trifluorobenzylcarbamoyl, group 2,4,6-trichloro benzylcarbamoyl, group 4-isopropylbenzylcarbamoyl, group 4-n-butylbenzylcarbamoyl, group 4-methylbenzylcarbamoyl, group 2

methylbenzylcarbamoyl, group 2,4-dimethylbenzylcarbamoyl, group 2.3- dimethylbenzylcarbamoyl, group 2,6-dimethylbenzylcarbamoyl, group 3.5- dimethylbenzylcarbamoyl, group 2,5-dimethylbenzylcarbamoyl, group 2.4.6- trimethylbenzylcarbamoyl, group 3,5-ditrifluoromethylbenzylcarbamoyl, group 4- isopropylbenzylcarbamoyl, group 4-n-butoxybenzylcarbamoyl, group 4- methoxybenzylcarbamoyl, group 2-methoxybenzylcarbamoyl, group 3- methoxybenzylcarbamoyl, group 2,4-dimethoxybenzylcarbamoyl, group 2.3- dimethoxybenzylcarbamoyl, group 2,6-dimethoxybenzylcarbamoyl, group 3.5- dimethoxybenzylcarbamoyl, group 2,5-dimethoxybenzylcarbamoyl, group 2.4.6-

trimethoxybenzylcarbamoyl, group 3,5-ditrifluoromethoxybenzylcarbamoyl, group 2isopropoxybenzylcarbamoyl, group 3-chloro-4-methoxybenzylcarbamoyl, group 2-chloro-4trifluoromethoxybenzylcarbamyl, 3-group-3-trifluoro-methyl-4-fluorobenzylcarbonyl, group 3 3-trifluoromethylbenzylcarbamoyl, group 4-trifluoromethylbenzylcarbamoyl, group

2-pentafluoroetilbenzilcarbamoíla group, 3-pentafluoroetilbenzilcarbamoíla group, 4pentafluoroetilbenzilcarbamoíla group, 2-trifluorometoxibenzilcarbamoíla, 3trifluorometoxibenzilcarbamoíla group, 4-trifluorometoxibenzilcarbamoíla group, 2pentafluoroetoxibenzilcarbamoíla, 3-pentafluoroetoxibenzilcarbamoíla group, 4pentafluoroetoxibenzilcarbamoíla group, 2- (2-trifluoromethylphenyl) etilcarbamoíla group, 2- ( 3-trifluoromethylphenyl) ethylcarbamoyl, group 2- (4-trifluoromethylphenyl) ethylcarbamoyl, group 2- (2-trifluoromethoxyphenyl) ethylcarbamoyl, group 2- (3- trifluoromethoxyphenyl) ethylcarbamoyl, group 2- (4-trifluoromethyl) 2-pentafluoroethoxyphenyl) ethylcarbamoyl, group 2- (3pentafluoroethoxyphenyl) ethylcarbamoyl, group 2- (4-pentafluoroethoxyphenyl) ethylcarbamoyl, group 3- (2-trifluoromethylphenyl) propylcarbamyl, group 3- (3tnflamethyl) propylcarbamoyl, group 3- (2-trifluoromethoxyphenyl) propylcar bamoíla, grupo 3- (3Petition 870190039560, of 26/04/2019, p. 172/876

164/854 trifluoromethoxyphenyl) propylcarbamoyl, group 3- (4-trifluoromethoxyphenyl) propylcarbamoyl, group 3- (3-pentafluoroethoxyphenyl) propylcarbamoyl, group 3- (4pentafluoroethoxyphenyl) propylcarbamoyl, group 4- (3) pentylcarbamoyl, group 4- (4-trifluoromethylphenyl) pentylcarbamoyl, group4- (4trifluoromethoxyphenyl) pentylcarbamoyl, group 6- (3-trifluoromethylphenyl) hexylcarbamoyl, group 6- (4-trifluoromethylphenyl) hexylcarbamoyl) hexylcarbamoyl (6).

[0241] A benzofuryl-substituted C1-6 alkoxycarbonyl group that can be substituted on the benzofuran ring by at least one halogen atom includes a benzofuryl-substituted C1-6 alkoxycarbonyl group that can be substituted on the benzofuran ring by 1 to 3 atoms halogen, for example, a 2benzofurylmethoxycarbonyl group, group 1- (2-benzofuryl) ethoxycarbonyl, group 2- (4benzofuryl) ethoxycarbonyl, group 3- (5-benzofuryl) propoxycarbonyl, group 4- (6benzofuryl) butoxycarbonyl, group 5- (7 -benzofuryl) pentyloxycarbonyl, group 6- (2benzofuryl) hexyloxycarbonyl, group 4-fluoro-2-benzofurylmethoxycarbonyl, group 5fluoro-2-benzofurylmethoxycarbonyl, group 6-fluoro-2-benzofurylmethoxycarbonyl, group

7-fluoro-2-benzofurylmethoxycarbonyl, group 4-chloro-2-benzofurylmethoxycarbonyl, group 5-chloro-2-benzofurylmethoxycarbonyl, group 6-chloro-2-benzofurylmethoxycarbonyl, group 7-chloro-2-benzofurylmethoxycarbonyl, group 4bromo-2-benzofuryl , 5-bromo-2-benzofurylmethoxycarbonyl group, 6-bromo-2-benzofurylmethoxycarbonyl group, 7-bromo-2benzofurylmethoxycarbonyl group, 4-iodo-2-benzofurylmethoxycarbonyl group, 5-iodo-2benzofurylmethoxycarbonyl group, 6-iodo-group , group 7-iodo-2benzofurylmethoxycarbonyl, group 4-fluoro-3-benzofurylmethoxycarbonyl, group 5-fluoro-

3-benzofurylmethoxycarbonyl, 6-fluoro-3-benzofurylmethoxycarbonyl group, 7fluoro-3-benzofurylmethoxycarbonyl group, 4-chloro-3-benzofurylmethoxycarbonyl group, 5-chloro-3-benzofurylmethoxycarbonyl group, 6-chloro-3-benzofuryl group 3-benzofurylmethoxycarbonyl, group 4bromo-3-benzofurylmethoxycarbonyl, group 5-bromo-3-benzofurylmethoxycarbonyl,

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165/854 6-bromo-3-benzofurylmethoxycarbonyl group, 7-bromo-3benzofurylmethoxycarbonyl group, 4-iodo-3-benzofurylmethoxycarbonyl group, 5-iodo-3benzofurylmethoxycarbonyl group, 6-iodo-3-benzofurylmethoxycarbonyl group 3 , group 2- (4-fluoro-2-benzofuryl) ethoxycarbonyl, group 2- (5fluoro-2-benzofuryl) ethoxycarbonyl, group 2- (6-fluoro-2-benzofuryl) ethoxycarbonyl, group 2- (7-fluoro-2 -benzofuryl) ethoxycarbonyl, group 2- (4-chloro-2-benzofuryl) ethoxycarbonyl, group 2- (5-chloro-2-benzofuryl) ethoxycarbonyl, group 2- (6-chloro-2benzofuryl) ethoxycarbonyl, group 2- (7 -chloro-2-benzofuryl) ethoxycarbonyl, group 2- (4-fluoro-3-benzofuryl) ethoxycarbonyl, group 2- (5-fluoro-3-benzofuryl) ethoxycarbonyl, group 2- (6-fluoro-3-benzofuryl) ethoxycarbonyl, group 2- (7-fluoro-3-benzofuryl) ethoxycarbonyl, group 2- (4-chloro-3-benzofuryl) ethoxycarbonyl, group 2- (5-chloro-3benzofuryl) ethoxycarbonyl, group 2- (6-chloro-3-benzofuryl ) ethoxycarbonyl, group 2- (7chloro-3-benzofuryl) ethoxycarbonyl, gr upo 6- (4-fluoro-2-benzofuryl) hexyloxycarbonyl, group 6- (5-fluoro-2-benzofuryl) hexyloxycarbonyl, group 6- (6-fluoro-2benzofuryl) hexyloxycarbonyl, group 6- (7-fluoro-2- benzofuryl) hexyloxycarbonyl, group 6 (4-chloro-2-benzofuryl) hexyloxycarbonyl, group 6- (5-chloro-2-benzofuryl) hexyloxycarbonyl, group 6- (6-chloro-2-benzofuryl) hexyloxycarbonyl, group 6- (7 -chloro-2benzofuryl) hexyloxycarbonyl, group 6- (4-fluoro-3-benzofuryl) ethoxycarbonyl, group 6- (5fluoro-3-benzofuryl) hexyloxycarbonyl, group 6- (6-fluoro-3-benzofuryl) hexyloxycarbonyl, group 6- (7-fluoro-3-benzofuryl) hexyloxycarbonyl, group 6- (4-chloro-3benzofuryl) hexyloxycarbonyl, group 6- (5-chloro-3-benzofuryl) hexyloxycarbonyl, group 6 (6-chloro-3-benzofuryl) hexyloxycarbonyl, 6- (7-chloro-3-benzofuryl) hexyloxycarbonyl group, (2,4-dibromo-3-benzofuryl) methoxycarbonyl group, (4,5,6-trichloro-3benzofuryl) methoxycarbonyl group or the like.

[0242] A C 1-6 benzothienyl alkoxycarbonyl group (which can be substituted on the benzothiophene ring by at least one group selected from a group consisting of a halogen atom and C 1-6 alkoxy group unsubstituted or substituted by halogen as a substituent) includes a C 1-6 alkoxycarbonyl benzothienyl group (which can be substituted on the benzothiophene ring by 1 to 3 groups selected from a group consisting of a halogen atom and an unsubstituted C 1-6 alkoxy group or

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166/854 replaced by halogen as a substituent), for example, a group

2benzothienylmethoxycarbonyl, group 3-benzothienylmethoxycarbonyl, group 4benzothienylmethoxycarbonyl, group 5-benzothienylmethoxycarbonyl, group 6benzothienylmethoxycarbonyl, group 7-benzothienylmethoxycarbonyl, group 2- (2benzothienyl) ethoxycarbonyl, group 3- (2) 5- (2-benzothienyl) pentyloxycarbonyl, group 6- (2benzothienyl) hexyloxycarbonyl, group 5-trifluoromethoxy-2-benzothienylmethoxycarbonyl, group 5-trifluoromethoxy-3-benzothienylmethoxycarbonyl, group 5-trifluoromethoxy-4-benzylmethyl-5-benzylmethyl , 3-trifluoromethoxy-6-benzothienylmethoxycarbonyl group, 2-trifluoromethoxy-7benzothienylmethoxycarbonyl group, 2-methoxy-7-benzothienylmethoxycarbonyl group, 5,6dimethoxy-3-benzothienylmethoxycarbonyl group, 2,5,6-trimethylmethoxy-3-group -6-methoxy-3-benzothienylmethoxycarbonyl, group 2- (4-ethoxy-2-benzothienyl) ethoxycarbonyl, group 5-chloro- 3 benzothienylmethoxycarbonyl, group 3,4-dibromo-2-benzothienylmethoxycarbonyl, group

4,5,6-trichloro-2-benzothienylmethoxycarbonyl, 5-trifluoromethoxy-2-chloro-7benzothienylmethoxycarbonyl group or the like.

[0243] Examples of a naphthyl-substituted C1-6 alkoxycarbonyl group include a 1-naphthylmethoxycarbonyl group, 2-naphthylmethoxycarbonyl group, group 2- (1-

naphthyl) ethoxycarbonyl, group 2- (2-naphthyl) ethoxycarbonyl, group 3- (1- naphthyl) propoxycarbonyl, group 3- (2-naphthyl) propoxycarbonyl, group 4- (1- naphthyl) butoxycarbonyl, group 4- (2-naphthyl) butoxycarbonyl, group 5- (1- naphthyl) pentoxycarbonyl, group 5- (2-naphthyl) pentoxycarbonyl, group 6- (1-

naphthyl) hexyloxycarbonyl, group 6- (2-naphthyl) hexyloxycarbonyl or the like.

[0244] A C1-6 alkoxycarbonyl group substituted by pyridyl (which can be substituted on the pyridine ring by at least one halogen atom as a substituent) includes a C1-6 alkoxycarbonyl group substituted by pyridyl (which can be substituted on the pyridine ring by 1 to 3 halogen atoms as a substituent), for example, a 2-pyridylmethoxycarbonyl group, 3-pyridylmethoxycarbonyl group,

4-pyridylmethoxycarbonyl, group 2- (2-pyridyl) ethoxycarbonyl, group 2- (3-

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167/854

pyridyl) ethoxycarbonyl, group 2- (4-pyridyl) ethoxycarbonyl, group 3- (2- pyridyl) propoxycarbonyl, group 3- (3-pyridyl) propoxycarbonyl, group 3- (4- pyridyl) propoxycarbonyl, group 4- (2-pyridyl) butoxycarbonyl, group 4- (3- pyridyl) butoxycarbonyl, group 4- (4-pyridyl) butoxycarbonyl, group 5- (2- pyridyl) pentyloxycarbonyl, group 5- (3-pyridyl) pentyloxycarbonyl, group 5- (4- pyridyl) pentyloxycarbonyl, group 6- (2-pyridyl) hexyloxycarbonyl, group 6- (3- pyridyl) hexyloxycarbonyl, group 6- (4-pyridyl) hexyloxycarbonyl, group 2-chloro-3-

pyridylmethoxycarbonyl, group 3-bromo-2-pyridylmethoxycarbonyl, group 4-fluoro-2pyridylmethoxycarbonyl, group 2- (2-chloro-4-pyridyl) ethoxycarbonyl, group 2- (3-chloro-5pyridyl) ethoxycarbonyl, group 2- (4- iodo-3-pyridyl) ethoxycarbonyl, group 3- (2-bromo-5pyridyl) propoxycarbonyl, group 3- (3-fluoro-4-pyridyl) propoxycarbonyl, group 3- (4-chloro2-pyridyl) propoxycarbonyl, group 4- ( 2-iodo-5-pyridyl) butoxycarbonyl, group 4- (3-bromo-

5-pyridyl) butoxycarbonyl, group 4- (4-chloro-5-pindyl) butoxycarbonyl, group 5- (2-chloro-5pyridyl) pentyloxycarbonyl, group 5- (3-fluoro-2-pyridyl) pentyloxycarbonyl, group 5- ( 4bromo-2-pyridyl) pentyloxycarbonyl, group 6- (2-chloro-5-pyridyl) hexyloxycarbonyl, group 6 (3-fluoro-4-pyridyl) hexyloxycarbonyl, group 6- (4-bromo-2-pyridyl) hexyloxycarbonyl, group (2,6-dichloro-4-pyridyl) methoxycarbonyl, group (2,3,4-trichloro-6-pyridyl) methoxycarbonyl or the like.

[0245] A C1-6 alkoxycarbonyl group substituted by furyl (which can be substituted on the furan ring by at least one nitro group as a substituent) includes a C1-6 alkoxycarbonyl group substituted by furil (which can be substituted on the furan ring by 1 to 3 nitro groups as a substituent), for example, a furylmethoxycarbonyl group 2, 3-furylmethoxycarbonyl group, 2- (2-furyl) ethoxycarbonyl group, 3- (2-furyl) propoxycarbonyl, furyl) butoxycarbonyl, furyl) pentyloxycarbonyl group, furyl) hexyloxycarbonyl, furylmethoxycarbonyl, furyl) ethoxycarbonyl, furyl) butoxycarbonyl, group group 3- (3-furyl) propoxycarbonyl, group

4- (3-furyl) butoxycarbonyl,

5- (3-furyl) pentyloxycarbonyl,

6- (3-furyl) hexyloxycarbonyl, 5-nitro-3-furylmethoxycarbonyl,

3- (5-nitro-2-furyl) propoxycarbonyl,

4- (5-nitro-3-furyl) butoxycarbonyl, group group group

4- (2-

5- (2-

6- (2- group group group group group group group group group

5-nitro-22- (5-nitro-2-

4- (5-nitro-2-

5- (5-nitro-2-

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168/854 furyl) pentyloxycarbonyl, group 5- (5-nitro-3-furyl) pentyloxycarbonyl, group 6- (5-nitro-2-furyl) hexyloxycarbonyl, group 6- (5-nitro-3-furyl) hexyloxycarbonyl, group (4 , 5-dinitro-2-furyl) methoxycarbonyl, (2,4,5-trinitro-3-funl) methoxycarbonyl group or the like.

[0246] A C1-6 alkoxycarbonyl group substituted by thienyl (which can be substituted on the thiophene ring by at least one halogen atom as a substituent) includes a C1-6 alkoxycarbonyl group substituted by thienyl (which can be substituted on the thiophene ring by 1 to 3 halogen atoms as a substituent), for example, a 2-thienylmethoxycarbonyl group, 3-thienylmethoxycarbonyl group, group 2-

(2-thienyl) ethoxycarbonyl, group 3- (2-thienyl) propoxycarbonyl, group 3- (3- thienyl) propoxycarbonyl, group 4- (2-thienyl) butoxycarbonyl, group 4- (3- thienyl) butoxycarbonyl, group 5- (2-thienyl) pentyloxycarbonyl, group 5- (3- thienyl) pentyloxycarbonyl, group 6- (2-thienyl) hexyloxycarbonyl, group 6- (3- thienyl) hexyloxycarbonyl, group 5-chloro-2-thienylmethoxycarbonyl, group 5-chloro-3-

thienylmethoxycarbonyl, group 2- (4-bromo-2-thienyl) ethoxycarbonyl, group 3- (3-fluoro-2thienyl) propoxycarbonyl, group 4- (5-iodo-2-thienyl) butoxycarbonyl, group 4- (4-chloro- 3thienyl) butoxycarbonyl, group 5- (3-chloro-2-thienyl) pentyloxycarbonyl, group 5- (2-chloro-3thienyl) pentyloxycarbonyl, group 6- (3-chloro-2-thienyl) hexyloxycarbonyl, group 6- (5- chloro-3-thienyl) hexyloxycarbonyl, (4,5-dichloro-2-thienyl) methoxycarbonyl group, (2,4,5trichloro-3-thienyl) methoxycarbonyl group or the like.

[0247] A C1-6 alkoxycarbonyl group substituted by thiazolyl (which can be substituted on the thiazole ring by at least one group selected from a group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted on the phenyl ring) by a C1-6 alkyl group unsubstituted or substituted by halogen)) includes a C1-6 alkoxycarbonyl group substituted by thiazolyl (which can be substituted on the thiazole ring by 1 to 2 groups selected from a group consisting of a C1 alkyl group -6 and a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 C1-6 alkyl groups unsubstituted or substituted by halogen)), for example, a 2-thiazolylmethoxycarbonyl group, group 2- (2-thiazolyl) ethoxycarbonyl, group 3- (2-thiazolyl) propoxycarbonyl, group 4- (2-thiazolyl) butoxycarbonyl, group 5- (2-thiazolyl) pentyloxycarbonyl, group 6- (2-thiazolyl) hexyloxycarbonyl, group 4Petition 870190039560 , of 26/04/2019, p. 177/876

169/854

thiazolylmethoxycarbonyl, 5-thiazolylmethoxycarbonyl group, 2-methyl-4- group thiazolylmethoxycarbonyl, 2-methyl-5-thiazolylmethoxycarbonyl group, 5-methyl-2- group thiazolylmethoxycarbonyl, 4-methyl-2-thiazolylmethoxycarbonyl group, 5-methyl-4- group thiazolylmethoxycarbonyl, 4-methyl-5-thiazolylmethoxycarbonyl group, 2-ethyl-4- group thiazolylmethoxycarbonyl, 2-ethyl-5-thiazolylmethoxycarbonyl group, 5-ethyl-2- group thiazolylmethoxycarbonyl, 5-propyl-2-thiazolylmethoxycarbonyl group, 4-n-butyl-2- group thiazolylmethoxycarbonyl, 5-ethyl-4-thiazolylmethoxycarbonyl group, 4-n-pentyl-5- group thiazolylmethoxycarbonyl, group 2-n-hexyl-4-thiazolylmethoxycarbonyl, group 2-n-hexyl-5- thiazolylmethoxycarbonyl, 4-n-pentyl-2-thiazolylmethoxycarbonyl group, 5-n-hexyl-2- group thiazolylmethoxycarbonyl, group 4-n-hexyl-2-thiazolylmethoxycarbonyl, group 5-n-hexyl-4- thiazolylmethoxycarbonyl, group 4-n-hexyl-5-thiazolylmethoxycarbonyl, group 2-phenyl-4- thiazolylmethoxycarbonyl, 2-phenyl-5-thiazolylmethoxycarbonyl group, 2-phenyl-4- group thiazolylmethoxycarbonyl, 4-phenyl-2-thiazolylmethoxycarbonyl group, 5-phenyl-2- group thiazolylmethoxycarbonyl, group 2- (4-phenyl-2-thiazolyl) ethoxycarbonyl, group 5-phenyl-4-

thiazolylmethoxycarbonyl, group 4-phenyl-5-thiazolylmethoxycarbonyl, group 5- (2-fluorophenyl) -

2-thiazolylmethoxycarbonyl, group 5- (2-fluorophenyl) -4-thiazolylmethoxycarbonyl, group 4- (2fluorophenyl) -5-thiazolylmethoxycarbonyl, group 2- (2-bromophenyl) -4-thiazolylmethoxycarbonyl, group 2- (2-fluorophenyl) - 5-thiazolylmethoxycarbonyl, group 2- (3-chlorophenyl) -4thiazolylmethoxycarbonyl, group 2- (2,3-difluorophenyl) -5-thiazolylmethoxycarbonyl, group 2 (2,4-dibromophenyl) -4-thiazolylmethoxycarbonyl, group 4- (2, 5-dichlorophenyl) -5-thiazolylmethoxycarbonyl, group 2- (2-chlorophenyl) -4-thiazolylmethoxycarbonyl, group 2- (2,4,6trichlorophenyl) -5-thiazolylmethoxycarbonyl, group 2- (4-chlorophenyl) -4-thiazolylmethoxycarbonyl, group 2- (2-fluorophenyl) -5-thiazolylmethoxycarbonyl, group 2- (4-chlorophenyl) -5thiazolylmethoxycarbonyl, group 2- (2,4-dichlorophenyl) -5-thiazolylmethoxycarbonyl, group 4- (2methylphenyl) -5-thiazolylmethoxycarbonyl, group 2- (2-ethylphenyl) -4-thiazolylmethoxycarbonyl, group 2- (2-n-propylphenyl) -5-thiazolylmethoxycarbonyl, group 2- (3-isopropylphenyl) -4 thiazolylmethoxycarbonyl, group 2- (3-n-butylphenyl) -5-thiazolylmethoxycar bonila, group 2- (4-n-pentylphenyl) -4-thiazolylmethoxycarbonyl, group 4- (2-n-hexylphenyl) -5-thiazolylmethoxycarbonyl, group 2- (2,4-dimethylphenyl) -4-thiazolylmethoxycarbonyl, group 2- (2 , 3-dimethylphenyl) -5thiazolylmethoxycarbonyl, group 2- (2,4,6-trimethylphenyl) -4-thiazolylmethoxycarbonyl, group 2

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170/854 (2-methylphenyl) -4-methyl-5-thiazolylmethoxycarbonyl, group 2- (4-chlorophenyl) -5-methyl-4thiazolylmethoxycarbonyl, group 2,4-dimethyl-5-thiazolylmethoxycarbonyl, group 5- (2trifluoromethylphenyl) - 2-thiazolylmethoxycarbonyl, group 5- (2-trifluoromethylphenyl) -4thiazolylmethoxycarbonyl, group 4- (2-trifluoromethylphenyl) -5-thiazolylmethoxycarbonyl, group 2- (2-trifluoromethylphenyl) -4-thiazolylmethoxycarbonyl, group 2- (2) 5thiazolylmethoxycarbonyl, group 2- (3-trifluoromethylphenyl) -4-thiazolylmethoxycarbonyl, group 2- (3-trifluoromethylphenyl) -5-thiazolylmethoxycarbonyl, group 2- (4-trifluoromethylphenyl) -4thiazolylmethoxycarbonyl or similar.

[0248] A C1-6 alkoxycarbonyl group substituted by tetrazolyl (which can be substituted on the tetrazole ring by at least one group selected from a group consisting of a C1-6 alkyl group and a phenyl group which can have at least one atom of halogen as a substituent on the phenyl ring as a substituent) includes a C1-6 alkoxycarbonyl group substituted by tetrazolyl (which can be substituted on the tetrazole ring by a group selected from a group consisting of a C1-6 alkyl group and a phenyl group that may have from 1 to 5, preferably from 1 to 3 halogen atoms as a substituent on the phenyl ring, as a substituent), for example, a 5- (1 H) -tetrazolylmethoxycarbonyl group, group 2- (5- (1 H) tetrazolyl) ethoxycarbonyl, group 3- (5- (1 H) -tetrazolyl) propoxycarbonyl, group 4- (5- (1 H) tetrazolyl) butoxycarbonyl, group 5- (5- (1 H) -tetrazolyl) pentyloxycarbonyl, group 6- (5 (1 H) -tetrazolyl) hexyloxycarbonyl, group 1-methyl-5- (1 H) -tetrazolylmethoxycarbonyl, group 1-ethyl-5- (1 H) -tetrazolylmethoxycarbonyl, group 1 -n-propi 1-5- (1 H) tetrazolylmethoxycarbonyl, group 1-n-butyl-5- (1H) -tetrazolylmethoxycarbonyl, group 1-npentyl -5- (1 H) -tetrazolylmethoxycarbonyl, group 1-n-hexyl-5- (1 H) tetrazolylmethoxycarbonyl, group 1-phenyl-5- (1 H) -tetrazolylmethoxycarbonyl, group 1- (2fluorophenyl) -5- (1 H) -tetrazolylmethoxycarbonyl, group 1- (3-fluorophenyl) -5- (1 H) tetrazolylmethoxycarbonyl, group 1- (4-fluorophenyl) -5- (1 H) -tetrazolylmethoxycarbonyl, group 1- (2-chlorophenyl) -5 - (1 H) -tetrazolylmethoxycarbonyl, group 1- (3-chlorophenyl) -5- (1 H) tetrazolylmethoxycarbonyl, group 1- (4-chlorophenyl) -5- (1 H) -tetrazolylmethoxycarbonyl, group 1 - (2-bromophenyl ) -5- (1 H) -tetrazolylmethoxycarbonyl, group 1 - (3-bromophenyl) -5- (1 H) tetrazolylmethoxycarbonyl, group 1- (4-bromophenyl) -5- (1 H) -tetrazolylmethoxycarbonyl,

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171/854 group 2- (1-methyl-5- (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1-ethyl-5- (1 H) tetrazolyl) ethoxycarbonyl, group 2- (1-propyl-5- (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1butyl-5- (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1-pentyl-5- (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1 -hexyl-5- (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1-pheni 1-5- (1 H) tetrazolyl) ethoxycarbonyl, group 2- (1- (2,4-difluorophenyl) -5- ( 1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1- (3-fluorophenyl) -5- (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1- (4-fluorophenyl) -5 (1 H) -tetrazolyl ) ethoxycarbonyl, group 2- (1 - (2,4,6-trichloropheni 1) -5- (1H) tetrazolyl) ethoxycarbonyl, group 2- (1- (3-chlorophenyl) -5- (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1- (4-chlorophenyl) -5- (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1- (2-bromophenyl) -5 (1 H) -tetrazolyl) ethoxycarbonyl, group 2- (1- (3-bromophenyl) -5- (1 H) tetrazolyl) ethoxycarbonyl, group 2- (1- (4-bromophenyl) -5- (1 H) -tetrazolyl) ethoxycarbonyl or the like.

[0249] Examples of a 2,3-dihydro-1 H-indenyloxycarbonyl group include a group

2,3-dihydro-1 H-inden-1-yloxycarbonyl, 2,3-dihydro-1 H-inden-2-yloxycarbonyl group or the like.

[0250] Examples of a C1-6 alkoxycarbonyl group substituted by adamantane include an adamantane-1-ylmethoxycarbonyl group, group 2- (adamantane-1yl) ethoxycarbonyl, group 3- (adamantane-1-yl) propoxycarbonyl, group 4- (adamantane -1yl) butoxycarbonyl, group 5- (adamantane-1-yl) pentyloxycarbonyl, group 6- (adamantane-

1-yl) hexyloxycarbonyl or the like.

[0251] Examples of a C3-6 phenyl alkynyloxycarbonyl group include a 2-phenylethynyloxycarbonyl group, 3-phenyl-2-propynyloxycarbonyl group, 4-phenyl-3-butin-1yloxycarbonyl group, 4-phenyl-3-butino-2-yloxycarbonyl group, 5-phenyl-4-pentin-1yloxycarbonyl group, 6-phenyl-5-hexin-1-yloxycarbonyl group or the like.

[0252] Examples of a C 1-6 alkoxycarbonyl phenylthio group include a phenylthiomethoxycarbonyl group, 2-phenylthioethoxycarbonyl group, 1-phenylthioethoxycarbonyl group, 3- (phenylthio) propoxycarbonyl group, 4- (phenylthio) butoxycarbonyl group, group 5 (phenylthio) pentyloxycarbonyl, group 6- (phenylthio) hexyloxycarbonyl or the like.

[0253] Examples of a C1-6 alkoxycarbonyl group substituted by phenyl C1-6 alkoxy include a benzyloxymethoxycarbonyl group, 2-benzyloxyethoxycarbonyl group, group 3

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172/854 (benzyloxy) propoxycarbonyl, group 4- (benzyloxy) butoxycarbonyl, group 5 (benzyloxy) pentyloxycarbonyl, group 6- (benzyloxy) hexyloxycarbonyl, group 2-phenylethoxyethoxycarbonyl, group 2-phenylethoxyethoxycarbonyl, group 3- (2-phenylethoxyoxy) group 4- (2-phenyloxy) butoxycarbonyl, group 5- (2-phenyloxy) pentyloxycarbonyl, group 6- (2-phenylethoxy) hexyloxycarbonyl, group 3-phenylpropoxymethoxycarbonyl, group 3-phenylpropoxyethoxycarbonyl, group 3- (3-phenylpropoxy) propoxycarbonyl, group 4- (3-) , group 5- (3-phenylpropoxy) pentyloxycarbonyl, group 6- (3-phenylpropoxy) hexyloxycarbonyl, group 4-phenylbutoxymethoxycarbonyl, group 4-phenyl-butoxyethoxycarbonyl, group 3- (4-phenyl-butoxy) propoxycarbonyl, group 4- (4-phenyl-butoxy-butoxy-butoxy) ) pentyloxycarbonyl, group 6- (4-phenylbutoxy) hexyloxycarbonyl, group 5-phenylpentyloxymethoxycarbonyl, group 5-phenylpentyloxyethoxycarbonyl, group 3- (5-phenylpentyloxy) propoxycarbonyl, group 4- (5-fe nilpentyloxy) butoxycarbonyl, group 5- (5phenylpentyloxy) pentyloxycarbonyl, group 6- (5-phenylpentyloxy) hexyloxycarbonyl, group 6-phenylexyloxymethoxycarbonyl, group 6-phenylexyloxyethoxycarbonyl, group 3- (6-phenylexyloxy -oxycarbonyl) -oxycarbonyl) group - (6phenylexyloxy) pentyloxycarbonyl, group 6- (6-phenylexyloxy) hexyloxycarbonyl or similar. [0254] Examples of a C2-6 alkenyloxycarbonyl group include a vinyl oxycarbonyl group, 2-propenyloxycarbonyl group (common name: allyloxycarbonyl group), 2-butene-1-yloxycarbonyl group, 3-butene-1-yloxycarbonyl group, group 4- pentene-1yloxycarbonyl, 3-pentene-1-yloxycarbonyl group, 5-hexene-1-yloxycarbonyl group, 4-hexene-1-yloxycarbonyl group, 3-hexene-1-yloxycarbonyl group or the like.

[0255] Examples of a C2-6 alkynyloxycarbonyl group include an acetylenoxycarbonyl group, 2-propynyloxycarbonyl group, 2-butin-1-yloxycarbonyl group, 3-butin-1-yloxycarbonyl group, group 4-pentin-1-yloxycarbonyl, group 3 -pentin-1yloxycarbonyl, 5-hexin-1-yloxycarbonyl group, 4-hexin-1-yloxycarbonyl group, 3hexin-1-yloxycarbonyl group or the like.

[0256] Examples of a C1-6 alkoxycarbonyl group substituted by C3-8 cycloalkyl include a cyclopropylmethoxycarbonyl group, cyclobutylmethoxycarbonyl group, cyclopentylmethoxycarbonyl group, cyclohexylmethoxycarbonyl group, cycloPetition group 870190039560, from 26/04/2019, p. 181/876

173/854

heptylmethoxycarbonyl, group cyclooctylmethoxycarbonyl, group 2- cyclopropylethoxycarbonyl, group 2-cyclobutylethoxycarbonyl, group 2- cyclopentylethoxycarbonyl, group 2-cyclohexylethoxycarbonyl, group 2-cycle- heptyletoxycarbonyl, ( group 3-cyclopropylpropoxycarbonyl, group 3- cyclobutylpropoxycarbonyl, group 3-cyclopentylpropoxycarbonyl, group 3-cycle- hexylpropoxycarbonyl, group 3-cycloheptylpropoxycarbonyl, group 3- cyclooctylpropoxycarbonyl, group 4-cyclopropylbutoxycarbonyl, group 4- cyclobutyl butoxycarbonyl, group 4-cyclohexylbutoxycarbonyl, group 5-cycle-

hexylpentyloxycarbonyl, 6-cyclohexylexyloxycarbonyl group or the like.

[0257] Examples of a benzoyl-substituted C1-6 alkoxycarbonyl group include a benzoylmethoxycarbonyl group, 2-benzoyletoxycarbonyl group, group 1-

benzoyletoxycarbonyl, group 3- (benzoyl) propoxycarbonyl, group 4- (benzoyl) butoxycarbonyl, group 5- (benzoyl) pentyloxycarbonyl, group 6-

(benzoyl) hexyloxycarbonyl or the like.

[0258] Examples of a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) include a phenoxy group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, unsubstituted C 1 alkyl group or substituted by halogen and C1-6 alkoxy group not substituted or substituted by halogen), for example, a phenoxy group, 2-fluorophenoxy group, group

3-fluorophenoxy, 4-fluorophenoxy group, 2-chlorophenoxy group, 3-chlorophenoxy group, 4-chlorophenoxy group, 2-bromophenoxy group, 3-bromophenoxy group, 4-bromophenoxy group, group

2-iodophenoxy, 3-iodophenoxy group, 4-iodophenoxy group, 2,3-difluorophenoxy group, group

3,4-difluorophenoxy, 3,5-difluorophenoxy group, 2,4-difluorophenoxy group, 2,6difluorophenoxy group, 2,3-dichlorophenoxy group, 3,4-dichlorophenoxy group, 3,5 dichlorophenoxy group, 2,4-dichlorophenoxy group , 2,6-dichlorophenoxy group, 2,3,4trifluorophenoxy group, 3,4,5-trifluorophenoxy group, 3,4,5-trichlorophenoxy group, 2,4,6trifluorophenoxy group, group 2,3,4,5,6 -pentafluorophenoxy, group 2,4,6-trichlorophenoxy, group 2

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174/854 fluoro-4-chlorophenoxy, 2-fluoro-4-bromophenoxy group, 3-fluoro-4-chlorophenoxy group, 2-methylphenoxy group, 3-methylphenoxy group, 4-methylphenoxy group, 2,6-dimethylphenoxy group, group

2,4,6-trimethylphenoxy, 2-methyl-3-chlorophenoxy group, 3-methyl-4-chlorophenoxy group, 2chloro-4-methylphenoxy group, 2-methyl-3-fluorophenoxy group, 2-trifluoromethylphenoxy group, 3trifluoromethylphenoxy group, 4-trifluoromethylphenoxy group, 3,5-di (trifluoromethyl) phenoxy group, 3,4-di (trifluoromethyl) phenoxy group, 2,4-di (trifluoromethyl) phenoxy group, 2pentafluoroethylphenoxy group, 3-pentafluoroethylphenoxy group, 4-penta group , 2-isopropylphenoxy group, 3-isopropylphenoxy group, 4-isopropylphenoxy group, 2-terbuthyloxy group, 3-ter-butylphenoxy group, 4-ter-butylphenoxy group, 2-sec-butylphenoxy group, 3-sec-butylphenoxy group, group 4-sec-butylphenoxy, 4-n-butylphenoxy group, 4-npentylphenoxy group, 4-n-hexylphenoxy group, 2-n-heptafluoropropylphenoxy group, 3-nheptafluoropropylphenoxy group, 4-n-heptafluoxyphenoxypropyl group

4-hexylphenoxy, 2-methoxyphenoxy group, 3-methoxyphenoxy group, 4-methoxyphenoxy group, 2-methoxy-3-chlorophenoxy group, 2-fluoro-3-methoxyphenoxy group, 2-fluoro-4methoxyphenoxy group, 2-fluoro-4 group -bromophenoxy, 4-chloro-3-fluorophenoxy group, 2,3,4trichlorophenoxy group, 3,4,5-trifluorophenoxy group, 2,4,6-trichlorophenoxy group, 2,4dimethylphenoxy group, 2,3-dimethylphenoxy group, group 3,5-dimethylphenoxy, 2,5-dimethylphenoxy group, 4-isopropoxyphenoxy group, 4-n-butoxyphenoxy group, 2,4-dimethoxyphenoxy group, 2,3-dimethoxyphenoxy group, 3,5-dimethoxyphenoxy group, 2,5-dimethoxyphenoxy group , 2,4,6-trimethoxyphenoxy group, 3,5-di (trifluoromethoxy) phenoxy group, 3-chloro-4-methoxyphenoxy group, 2-chloro-4-trifluoromethoxyphenoxy group, 3-methyl-4-fluorophenoxy group, 4-bromo group -3trifluoromethylphenoxy, 2,6-dimethoxyphenoxy group, 2-trifluoromethoxyphenoxy group, 3trifluoromethoxyphenoxy group, 4-trifluoromethoxyphenoxy group, 2,3-di (trifluoromethoxy) phenoxy group, 2,4-di (trifluoromethoxy) phenoxy group, phenoxy group 2-pentafluoroethoxyphenoxy group, 3pentafluoroethoxyphenoxy group, 4-pentafluoroethoxyphenoxy group, 2-isopropoxyphenoxy group, 3-isopropoxyphenoxy group, 4-isopropoxyphenoxy group, 2-ter-butoxyphenoxy group, 2-ter-butoxyoxy group, 3-group-tert-butoxy group sec-butoxyphenoxy, 3-secbutoxyphenoxy group, 4-sec-butoxyphenoxy group, 4-n-hexyloxyphenoxy group, 2-nheptafluoropropoxyphenoxy group, 3-n-heptafluoropropoxyphenoxy group, similar 4-nheptafluoxyoxyoxyoxyoxyoxy or similar.

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175/854 [0259] Examples of an 8-azabicyclo [3,2,1] octyl group (which can be substituted on the 8-azabicyclo [3,2,1] octane ring by at least one phenoxy group (which can be substituted in the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen)) include an 8- azabicyclo [3,2,1] octyl (which can be substituted on the 8azabicyclo [3,2,1] octane ring with at least one phenoxy group (which can be substituted on the phenyl ring with from 1 to 5, preferably from 1 to 5) 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen)), for example, an 8-azabicyclo group [3 , 2,1] octan-8-yl, group 3-phenoxy-8azabicyclo [3,2,1] octan-8-yl, group 3- (3-chlorophenoxy) -8-azabicyclo [3,2, 1] octan-1-yl, group 3- (4-bromophenoxy) -8-azabicyclo [3,2,1] octan-8-yl, group 3- (2-fluorophenoxy) -8azabicyclo [3,2,1] octan-8-yl, group 3- (3-iodophenoxy) -8-azabicyclo [3,2,1] octan-8-yl, group 3- (3-trifluoromethylphenoxy) -8-azabicyclo [3,2,1] octan-1-yl, group 3- (3-methylphenoxy) -

8-azabicyclo [3,2,1] octan-1 -yl, group 3- (4-methoxyphenoxy) -8-azabicyclo [3,2,1] octan-1 -yl, group 3- (3,5-ditrifluoromethylphenoxy ) -8-azabicyclo [3,2,1] octan-1-yl, group 3- (3trifluoromethyl-4-fluorophenoxy) -8-azabicyclo [3,2,1] octan-1 -yl, group 3- (2 -trifluoromethoxy-

3-chlorophenoxy) -8-azabicyclo [3,2,1] octan-1 -yl, group 3- (2,4-difluorophenoxy) -8azabicyclo [3,2,1] octan-1 -yl, group 3- ( 2,4,6-trichlorophenoxy) -8-azabicyclo [3,2,1] octan-1-yl, group 3- (4-trifluoromethylphenoxy) -8-azabicyclo [3,2,1] octan-1-ila, group 3- (3trifluoromethoxyphenoxy) -8-azabicyclo [3,2,1] octan-1-yl, group 3- (4-trifluoromethoxyphenoxy) 8-azabicyclo [3,2,1] octan-1-yl or the like.

[0260] Examples of a group represented by a pyridyl group (which can be substituted on the pyridine ring by at least one unsubstituted C1-6 alkyl group or substituted by halogen as a substituent) include a pyridyl group (which can be substituted on the ring pyridine with 1 to 3 C1-6 alkyl groups unsubstituted or substituted by halogen as a substituent), for example, a pyridin-3-yl group, pyridin-2-yl group, pyridin-4-yl group, group 4- trifluoromethylpyridin-2-yl, group 4trifluoromethylpyridin-3-yl, group 5-trifluoromethylpindin-2-yl, group 5-trifluoromethylpyridinPetition 870190039560, of 26/04/2019, p. 184/876

176/854

3-yl, 2-trifluoromethylpyridin-3-yl group, 2,4-dimethylpyridin-3-yl group, 3,4,5-trimethylpyridin-2-yl group, 4-ethylpyridin-2-yl group, 3-n-butylpyridin group -2-yl, 5-n-pentylpyridin-2-yl group, 4-n-hexylpyridin-2-yl group or the like.

[0261] R ⁴⁷ and R ⁴⁸ can form a 5- to 7-membered saturated heterocycle through mutual bonding through or not through other heteroatoms together with the adjacent nitrogen atom. The heterocycle can be substituted by at least one phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, unsubstituted C1-6 alkyl group or substituted by halogen or alkoxy group C1-6 unsubstituted or substituted by halogen) as a substituent) and include the heterocycle (which can be substituted on the heterocycle ring by 1 to 3 phenyl groups (which can be substituted on the phenyl ring by 1 to 5, preferably from 1 to 3 groups selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group or an unsubstituted or substituted C1-6 alkoxy group) as a substituent), examples of which include a pyrrolidinyl group, morpholino group, thiomorpholino group, piperazil group, piperidyl group, homopiperazil group, 4-phenylpiperazin-1 -ila group, 4phenylpiperidin-1 -ila group, group 4- (3-chlorophenyl) piperazin-1-yl, group 4- (4-chlorophenyl) piperazin-1 -yl, group 4- (3,4-dichlorophenyl) piperazin-1 -yl, group 4- (3trifluoromethylphenyl) piperazin-1 -yl , group 4- (4-trifluoromethylphenyl) piperazin-1 -yl, group 4 (3-trifluoromethoxyphenyl) piperazin-1 -yl, group 4- (4-trifluoromethoxyphenyl) piperazin-1 -yl, group 4-phenylpiperidin-l -yl , group 4- (3-chlorophenyl) piperidin-1 -yl, group 4- (4-chlorophenyl) piperidin-1 -yl, group 4- (3,4-dichlorophenyl) piperidin-1 -yl, group 4- (3trifluoromethylphenyl) piperidin -1 -yl, group 4- (4-trifluoromethylphenyl) piperidin-1 -yl, group 4 (3-trifluoromethoxyphenyl) pipendin-1 -yl, group 4- (4-trifluoromethoxyphenyl) pipendin-1 -yl, group 4- ( 2,4,6-trifluorophenyl) piperazin-1 -yl, group 4- (4-methylphenyl) piperazin-1 -yl, group

4- (3-methoxyphenyl) piperazin-1-yl, group 4- (3,4-dimethoxyphenyl) piperazin-1-yl, group 4 (2,4-dimethylphenyl) piperazin-1-yl, group 4- (2, 4,6-trimethoxyphenyl) piperazin-1 -yl, group 4 (3,4,5-trimethylphenyl) piperazin-1 -yl, group 4- (2,4,6-trifluorophenyl) piperidin-1 -yl, group 4 ( 2,3,4,5,6-pentafluorophenyl) piperidin-1 -yl, group 4- (4-methylphenyl) piperidin-1 -yl, group 4

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177/854 (3-methoxyphenyl) piperidin-1-yl, group 4- (3,4-dimethoxyphenyl) piperidin-1-yl, group 4- (2,4-dimethylphenyl) piperidin-1-yl, group 4- (2, 4,6-trimethoxyphenyl) piperidin-1 -yl, group 4- (3,4,5trimethylphenyl) piperidin-1 -yl, group 3- (4-methylphenyl) morpholino, group 3- (3methoxyphenyl) pyrrolidinyl-1 -yl, 2- (4-methylphenyl) pyrrolidinyl-1-yl group, 4- (2,4,6-trimethoxyphenyl) homopiperazin-1-yl group, 4- (3,4,5-trimethylphenyl) thiomorpholine group, 2,4diphenylpiperazin-1 group -ila, group 2,4,6-triphenylpiperazin-1 -ila, group 4-phenylpiperazin-1 -ila, group 4-phenylpiperidin-1 -ila, group 3- (3-chlorophenyl) pyrrolidin-1 -ila, group 3 - (4chlorophenyl) morpholino, group 4- (3,4-dichlorophenyl) homopiperazin-1-yl, group 3- (3trifluoromethylphenyl) thiomorpholine, group 2- (4-trifluoromethylphenyl) pyrrolidin-1-yl, group 2- (3trifluoromethoxyphenyl) morpholino, group 3- (4-trifluoromethoxyphenyl) homopiperazin-1-yl, group 3-phenylpyrrolidin-1-yl, group 4- (3-chlorophenyl) morpholino, group 4- (4-chlorophenyl) homopiperidin-1-yl, group 3- (3,4-di chlorophenyl) thiomorpholine, group 3- (3-trifluoromethyl Ifen l) pyrrole id in-1-yl, group 4- (4-trifluoromethylphenyl) homopiperazin-1-yl, group 3-phenylthiomorpholine, group 4-phenylmorpholine or the like.

[0262] Examples of an amino substituted C2-6 group (which can be substituted in the amino group by at least one group selected from a group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted in the phenyl ring for at least one group selected from a group consisting of a halogen atom, halogen substituted or substituted C1-6 alkyl group and halogen substituted or substituted C1-6 alkoxy group)) include a C2- alkenyl group 6 substituted by amino (which can be substituted in the amino group by 1 to 2 groups selected from a group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted in the phenyl ring by 1 to 5, from preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen)), for example, an amino group ovinyl, 3-amino-2-propenyl group, 3-amino-1-propenyl group, 4-amino-3-butenyl group, 4 amino-3- butyl group, 5-amino-4-pentenyl group, 6-amino- group 5-hexenyl, methylaminovinyl group, 3-methylamino-2-propenyl group, 3-methylamino-1-propenyl group, 4-methylamino-3-butenyl group, 4-methylamino-3-butenyl group, 5-methylamino-4 group

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178/854 pentenyl, 6-methylamino-5-hexenyl group, methylaminovinyl group, 3-methylamino-

2- propenyl, 3-dimethylamino-2-propenyl group, 3-ethylamino-1-propenyl group, 3dethylamino-1-propenyl group, 4-ethylamino-3-butenyl group, 4-dimethylamino-3-butenyl group, group 4- diethylamino-3-butenyl, 5-ethylamino-4-pentenyl group, 6-ethylamino-5hexenyl group, n-propylaminovinyl group, 3-n-propylamino-2-propenyl group, 3-npropylamino-1-propenyl group, group 4- n-propylamino-3-butenyl, 4-n-propylamino-3butenyl group, 5-n-propylamino-4-pentenyl group, 6-n-propylamino-5-hexenyl group, n-butylaminovinyl group, 3-n-butylamino group -2-propenyl, group 3-n-butylamino-1propenyl, group 4-n-butylamino-3-butenyl, group 4-n-butylamino-3-butenyl, group 5n-butylamino-4-pentenyl, group 6-n- butylamino-5-hexenyl, n-pentylaminovinyl group, 3-n-pentylamino-2-propenyl group, 3-n-hexylamino-1-propenyl group, 4-nhexylamino-3-butenyl group, 4-n-hexylamino-3 group -butenyl, 5-n-hexylamino-4pentenyl group, 6-n-pentylamino-5-hexenyl group, phenylaminovinyl group, 3phenylamino-2-prop group enyl, 3-phenylamino-1-propenyl group, 4-phenylamino-3-butenyl group, 4-phenylamino-3-butenyl group, 5-phenylamino-4-pentenyl group, 6-phenylamino-5hexenyl group, 4-chlorophenylaminovinyl group, group 3- (4-bromophenyl) amino-2-propenyl, group 3- (2,4-dichlorophenyl) amino-1-propenyl, group 4- (2,4,6-trichlorophenyl) amino-3butenyl, group 4- ( 2,3,4,5,6-pentafluorophenyl) amino-3-butenyl, group 4- (4-fluorophenyl) amino-3-butenyl, group 5- (4-iodophenyl) amino-4-pentenyl, group 6- (4chlorophenyl) amino-5-hexenyl, (3-methylphenyl) aminovinyl group, (4trifluoromethylphenyl) aminovinyl group, group 3- (4-trifluoromethylphenyl) amino-2-propenyl, group

3- (4-trifluoromethylphenyl) amino-1-propenyl, group 4- (4-trifluoromethylphenyl) amino-3-butenyl, group 5- (3,4-dimethylphenyl) amino-4-pentenyl, group 6- (3,4 , 5trimethylphenyl) amino-5-hexenyl, (2-methoxyphenyl) aminovinyl group, (4trifluoromethoxyphenyl) aminovinyl group, group 3- (4-trifluoromethoxyphenyl) amino-2-propenyl, group 3- (3,5-dimethoxyphenyl) amino-1 -propenyl, group 4- (2,5-dimethoxyphenyl) amino-3butenyl, group 4- (2,4,6-trimethoxyphenyl) amino-3-butenyl, group 5- [N-methyl-N- (4trifluoromethylphenyl) amino] -4-pentenyl, group 6- [N-ethyl-N- (4-trifluoromethoxyphenyl) amino] -

5-hexenyl or the like.

[0263] Examples of an oxazolidinyl group (which can be substituted on the ring

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179/854 oxazolidine by at least one oxo group as a substituent) includes an oxazolidin-4-yl group, oxazolidin-5-yl group, 2-oxazolidin-4-yl group, 2-oxooxazolidin-5-yl group or the like.

[0264] Examples of a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen); halogen atom; C1-6 alkyl group unsubstituted or substituted by halogen ; C1-6 alkoxy group unsubstituted or substituted by halogen; amino group that can have at least one group selected from a group consisting of a C1-6 alkyl group and a phenyl C1-6 alkyl group (which can be substituted on the ring phenyl for at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group and an unsubstituted or substituted C1-6 alkoxy group halogen), a piperazine group (which can be substituted on the piperazine ring by at least one phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom) , a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent); and a piperidyl group (which can have at least one amino group which can have a group selected from a group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted on the phenyl ring by at least one selected group of a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent on the piperidine ring) include a phenyl C1-6 alkyl group ( which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a phenoxy group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group not

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180/854 substituted or substituted by halogen and C1-6 alkoxy group not substituted or substituted by halogen); halogen atom; C1-6 alkyl group unsubstituted or substituted by halogen; C1-6 alkoxy group unsubstituted or substituted by halogen; amino group that may have from 1 to 2 groups selected from a group consisting of a C1-6 alkyl group and a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen); a piperazinyl group (which can be substituted on the piperazine ring by 1 to 3 groups selected from a group consisting of a phenyl C 1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5, preferably from 1 to 5) 3 groups selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent); and a piperidyl group (which can have 1 to 3 amino groups which can have 1 to 2 groups selected from a group consisting of the C1-6 alkyl group and a phenyl group (which can be replaced on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent on the ring piperidine), for example, a benzyl group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 4-phenylpentyl group, group

6-phenylexyl, 2-fluorobenzyl, group 3-fluorobenzyl, group 4-fluorobenzyl, group 2chlorobenzyl, group 3-chlorobenzyl, group 4-chlorobenzyl, group 2-bromobenzyl, group 3-bromobenzyl, group 4-bromobenzyl, group 2-bromobenzyl, group 2-bromobenzyl , 3-iodobenzyl group, 4-iodobenzyl group, 2,3-difluorobenzyl group, 3,4-difluorobenzyl group, 3,5difluorobenzyl group, 2,3,4,5,6-pentafluorobenzyl group, 2,4-difluorobenzyl group, group

2,6-difluorobenzyl, 2,3-dichlorobenzyl group, 3,4-dichlorobenzyl group, 3,5-dichlorobenzyl group, 2,4-dichlorobenzyl group, 2,6-dichlorobenzyl group, 2-fluoro-4bromobenzyl group, 4-chlorine group -3-fluorobenzyl, group 2,3,4-trichlorobenzyl, group 3,4,5

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181/854 trifluorobenzyl, group 2,4,6-trichlorobenzyl, group 4-isopropylbenzyl, group 4-nbutylbenzyl, group 4-methylbenzyl, group 2-methylbenzyl, group 3-methylbenzyl, group

2,4-dimethylbenzyl, 2,3-dimethylbenzyl group, 2,6-dimethylbenzyl group, 3,5dimethylbenzyl group, 2,5-dimethylbenzyl group, 2,4,6-trimethylbenzyl group, 3,5ditrifluoromethylbenzyl group, 2,3 group , 4,5,6-pentafluorobenzyl, group 4-isopropoxybenzyl, group 4-n-butoxybenzyl, group 4-methoxybenzyl, group 2-methoxybenzyl, group 3-methoxybenzyl, group 2,4-dimethoxybenzyl, group 2,4-dimethoxybenzyl, group 2 , 6-dimethoxybenzyl, 3,5-dimethoxybenzyl group, 2,5-dimethoxybenzyl group, 2,4,6-trimethoxybenzyl group, 3,5-ditrifluoromethoxybenzyl group, 2-isopropoxybenzyl group, 3-chloro-4-methoxybenzyl group, 2-chloro-group 4-trifluoromethoxybenzyl, 3-methyl-4fluorobenzyl group, 4-bromo-3-trifluoromethylbenzyl group, 2-trifluoromethylbenzyl group, 3-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 2pentafluoro group, pentafluoroethyl group

group 2-trifluoromethoxybenzyl, group 3-trifluoromethoxybenzyl, group 4- trifluoromethoxybenzyl, group 2-pentafluoroethoxybenzyl, group 3- pentafluoroethoxybenzyl, group 4-pentafluoroethoxybenzyl, < group 2- (2- trifluoromethylphenyl) ethyl, group 2- (3-trifluoromethylphenyl) ethyl, group 2- (4- trifluoromethylphenyl) ethyl, group 2- (2-trifluoromethoxyphenyl) ethyl, group 2- (3- (trifluoromethoxyphenyl) ethyl, group 2- (3-trifluoromethoxyphenyl) ethyl, group 2- (2- pentafluoroethoxyphenyl) ethyl, group 2- (3-pentafluoroethoxyphenyl) ethyl, group 2- (4- pentafluoroethoxyphenyl) ethyl, group 3- (2-trifluoromethylphenyl) propyl, group 3- (3- trifluoromethylphenyl) propyl, group 3- (4-trifluoromethylphenyl) propyl, group 3- (2- trifluoromethoxyphenyl) propyl, group 3- (3-trifluoromethoxyphenyl) propyl, group 3- (4- trifluoromethoxyphenyl) propyl, group 3- (3-pentafluoroethoxyphenyl) propyl, group 3- (4- pentafluoroethoxyphenyl) propyl, group 4- (3-pentafluoroethoxyphenyl) butyl, group 5- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethoxyphenyl) pentyl, group 6- (3-trifluoromethylphenyl) hexyl, group 6- (4-

trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethoxyphenyl) hexyl, 2-aminobenzyl group, 2,4-diaminobenzyl group, 2,4,6-triaminobenzyl group, 2-methylaminobenzyl group, 2-benzylaminobenzyl group, 2-fluorobenzylamine group group 3 Petition 870190039560, of 26/04/2019, p. 190/876

182/854 fluorobenzylaminobenzyl, group 4-fluorobenzylaminobenzyl, group 2-chlorobenzyl, 3-

chlorobenzylaminobenzyl, group 4-chlorobenzylaminobenzyl, group 2- bromobenzylaminobenzyl, group 3-bromobenzylaminobenzyl, group 4- bromobenzylaminobenzyl, group 2-iodobenzylaminobenzyl, group 3- iodobenzylaminobenzyl, group 4-iodobenzylaminobenzyl, group 2.3- difluorobenzylaminobenzyl, group 3,4-difluorobenzylaminobenzyl, group 3.5- difluorobenzylaminobenzyl, group 2,3,4,5,6-pentafluorobenzylaminobenzyl, group 2,4- difluorobenzylaminobenzyl, group 2,6-difluorobenzylaminobenzyl, group 2.3- dichlorobenzylaminobenzyl, group 3,4-dichlorobenzylaminobenzyl, group 3.5- dichlorobenzylaminobenzyl, group 2,4-dichlorobenzylaminobenzyl, group 2.6- dichlorobenzylaminobenzyl, group 2-fluoro-4-bromobenzylaminobenzyl, group 4-chloro- 3-fluorobenzylaminobenzyl, group 2,3,4-trichlorobenzylaminobenzyl, group 3.4.5- trifluorobenzylaminobenzyl, group 2,4,6-trichlorobenzylaminobenzyl, group 4- isopropylbenzylaminobenzyl, 4-n-butylbenzylaminobenzyl group, group 4- methylbenzylaminobenzyl, group 2-methylbenzylaminobenzyl, group 3- methylbenzylaminobenzyl, group 2,4-dimethylbenzylaminobenzyl, group 2.3- dimethylbenzylaminobenzyl, group 2,6-dimethylbenzylaminobenzyl, group 3.5- dimethylbenzylaminobenzyl, 2,5-dimethylbenzylaminobenzyl group, group 2.4.6- trimethylbenzylaminobenzyl, group 3,5-ditrifluoromethylbenzylaminobenzyl, group 2,3,4,5,6-pentafluorobenzylaminobenzyl, group 4-isopropoxybenzylaminobenzyl, 4-n-butoxybenzylaminobenzyl group, group 4-methoxybenzylaminobenzyl, group 2- methoxybenzylaminobenzyl, group 3-methoxybenzylaminobenzyl, group 2.4- dimethoxybenzylaminobenzyl, group 2,3-dimethoxybenzylaminobenzyl, group 2.6- dimethoxybenzylaminobenzyl, group 3,5-dimethoxybenzylaminobenzyl, group 2.5-

dimethoxybenzylaminobenzyl,

2,4,6-trimethoxybenzylaminobenzyl,

3,5 group ditrifluoromethoxybenzylaminobenzyl group, 2-isopropoxybenzylaminobenzyl group, group 3 chloro-4-methoxybenzylaminobenzyl, group 2-chloro-4-trifluoromethoxybenzylaminobenzyl, group 3-methyl-4-fluorobenzylaminobenzyl-benzyl-methyl-3-group, group 4 3trifluoromethylbenzylaminobenzyl, group 4-trifluoromethylbenzylaminobenzyl, group 2Petition 870190039560, of 26/04/2019, p. 191/876

183/854 pentafluoroetoxibenzilaminobenzila group, 3-pentafluoroetoxibenzilaminobenzila, 4pentafluoroetoxibenzilaminobenzila group, 2trifluorometoxibenzilaminobenzila group, 3-trifluorometoxibenzilaminobenzila group, 4-trifluorometoxibenzilaminobenzila group, 2-pentafluoroetoxibenzilaminobenzila, 3-pentafluoroetoxibenzilaminobenzila group, 4pentafluoroetoxibenzilaminobenzila group, 3- (N-methyl-N -benzylamino) benzyl, group 4 (dibenzylamino) benzyl, group 2-dimethylaminobenzyl, group 3-dimethylaminobenzyl, group 4-dimethylaminobenzyl, group 2- (2-dimethylaminophenyl) ethyl, group 2- (3dimethylaminophenyl) ethyl, group 2- (4 -dimethylaminophenyl) ethyl, group 3- (2dimethylaminophenyl) propyl, group 3- (3-dimethylaminophenyl) propyl, group 3- (4dimethylaminophenyl) propyl, group 2-phenoxybenzyl, group 2,3-diphenoxybenzyl, group

2,4,6-triphenoxybenzyl, group 2- (2-fluorophenoxy) benzyl, group 3- (3-fluorophenoxy) benzyl, group 4- (4-fluorophenoxy) benzyl, group 2- (2-chlorophenoxy) benzyl, group 3 - (3-chlorophenoxy) benzyl, group 4- (4-chlorophenoxy) benzyl, group 2- (2-bromophenoxy) benzyl, group 3- (3-bromophenoxy) benzyl, group 4- (4-bromophenoxy) benzyl, group 2 - (2iodophenoxy) benzyl, group 3- (3-iodophenoxy) benzyl, group 4- (4-iodophenoxy) benzyl, group 3- (2,3-difluorophenoxy) benzyl, group 4- (3,4-difluorophenoxy) benzyl, group 2- (3,5difluorophenosxy) benzyl, group 4- (2,3,4,5,6-pentafluorophenoxy) benzyl, group 2- (2,4-

difluorophenoxy) benzyl, group 4- (2,6-difluorophenoxy) benzyl, group 3- (2,3- dichlorophenoxy) benzyl, group 2- (3,4-dichlorophenoxy) benzyl, group 4- (3.5- dichlorophenoxy) benzyl, group 3- (2,4-dichlorophenoxy) benzyl, group 4- (2,6- dichlorophenoxy) benzyl, i group 4- (2-fluoro-4-bromophenoxy) benzyl, group 3- (4-chloro-3- fluorophenoxy) benzyl, group 4- (2,3,4-trichlorophenoxy) benzyl, group 4- (3,4,5- trifluorophenoxy) benzyl, group 4- (2,4,6-trichlorophenoxy) benzyl, group 2- (4- isopropylphenoxy) benzyl, group 3- (4-n-butylphenoxy) benzyl, group 4- (4-

methylphenoxy) benzyl, group 3- (2-methylphenoxy) benzyl, group 2- (3-methylphenoxy) benzyl, group 2- (2,4-dimethylphenoxy) benzyl, group 3- (2,3-dimethylphenoxy) benzyl, group 4 - (2,6dimethylphenoxy) benzyl, group 2- (3,5-dimethylphenoxy) benzyl, group 3- (2,5dimethylphenoxy) benzyl, group 2- (2,4,6-trimethylphenoxy) benzyl, group 3- (3, 5ditrifluoromethylphenoxy) benzyl, group 4- (2,3,4,5,6-pentafluorophenoxy) benzyl, group 2- (4Petition 870190039560, from 26/04/2019, page 192/876

184/854 isopropoxyphenoxy) benzyl, methoxyphenoxy) benzyl, methoxyphenoxy) benzyl, dimethoxyphenoxy) benzyl, dimethoxyphenoxy) benzyl, trimethoxyphenoxy) benzyl, group group group group group group group group

2- (4-n-butoxyphenoxy) benzyl,

3- (2-methoxyphenoxy) benzyl,

2- (2,4-dimethoxyphenoxy) benzyl,

4- (2,6-dimethoxyphenoxy) benzyl,

3- (2,5-dimethoxyphenoxy) benzyl,

2- (3,5-ditrifluoromethoxyphenoxy) benzyl, group 3- (2group group group group group

2- (44- (33- (2,32- (3,54- (2,4,6isopropoxyphenoxy) benzyl, group 4- (3-chloro-4-methoxyphenoxy) benzyl, group 3- (2-chloro-4trifluoromethoxyphenoxy ) benzyl, group 2- (3-methyl-4-fluorophenoxy) benzyl, group 3- (4bromo-3-trifluoromethylphenoxy) benzyl, group 4- (2-trifluoromethylphenoxy) benzyl, group 2 (3-trifluoromethylphenoxy) benzyl, group 3 - (4-trifluoromethylphenoxy) benzyl, group 4- (2pentafluoromethylphenoxy) benzyl, group 2- (3-pentafluoroethylphenoxy) benzyl, group 3- (4pentafluoroethylphenoxy) benzyl, group 4- (2-trifluoromethoxyphenoxy) 2- benzyl, group 3- (4-trifluoromethoxyphenoxy) benzyl, group 4- (2pentafluoroethoxyphenoxy) benzyl, group 2- (3-pentafluoroethoxyphenoxy) benzyl, group 3- (4 pentafluoroethoxyphenoxy) benzyl, group 2- [3- (2-trifluoroethyl) phenyl phenyl] ethyl, group 2- [3 (3-trifluoromethylphenoxy) phenyl] ethyl, group 2- [4- (4-trifluoromethylphenoxy) phenyl] ethyl, group 3 [4- (2-trifluoromethylphenoxy) phenyl] propyl, group 4- [3- (3-pentafluoroethoxyphenoxy) phenyl] butyl, gr upo 5- [4- (4-trifluoromethylphenoxy) phenyl] pentyl, group 6- [2- (3 trifluoromethylphenoxy) phenyl] hexyl, group 4- (1-piperazinyl) benzyl, group 4- (1 piperidinyl) benzyl, group 4 - (4-benzyl-1-piperanzinyl) benzyl, group 4- (4- (3-chlorobenzyl)

1-piperanzinyl) benzyl, group 4- (4- (2,4-dimethylbenzyl) -1-piperanzinyl) benzyl, group 4 (4- (2,4-dimethylbenzyl) -1-piperanzinyl) benzyl, group 4- (2 , 4-dibenzyl-1piperanzinyl) benzyl, group 4- (2,3,4-tribenyl-1-piperanzinyl) benzyl, group 4- (4- (4trifluoromethyl Ibenzi) -1 -piperanzinyl) benzyl, group 4- ( 4-anilino-1-piperidyl) benzyl, group 4- (4- (3-trifluoromethylbenzyl) -1-piperanzinyl) benzyl, group 4- [4- (N-methylanilino) -1piperidinyl] benzyl, group 4- [4- (N-methyl-3-chloroanilino) -1-piperidinyl) benzyl, group 4- [4 (2,4-dimethylanyl) -1-piperidinyl] benzyl, group 4- [4- (N-methyl-2 , 4,6-trimethoxyanilino) -1 piperidinyl] benzyl, group 4- [4- (4-trifluoromethoxyanilino) -1-pipendinyl] benzyl, group 4 [4- (N-methyl-3-trifluoromethylanilino) -1 -piperid in il] benzyl, group 4- (3,4-dianyl-1-piperidinyl) benzyl, group 4- (3,4,5-trianilino-1-piperidinyl) benzyl or the like.

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185/854 [0265] Examples of a C1-6 alkyl amino group (which can be substituted in the amino group by at least one group selected from a group consisting of C1-6 alkyl group, C1-6 alkoxycarbonyl group and phenyl group which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom or an unsubstituted or substituted halogen C1-6 alkyl group) include a C1-6 alkyl amino group (which can be substituted on amino group by 1 to 2 groups selected from a group consisting of C1-6 alkyl groups, C1-6 alkoxycarbonyl group and phenyl groups that can be substituted in the phenyl group by 1 to 5, preferably 1 to 3 selected groups a group consisting of a halogen atom or an unsubstituted or substituted halogen C1-6 alkyl group), for example, an aminomethyl group, 2-aminoethyl group, 1aminoethyl group, 3-aminopropyl group, 4-aminobutyl group, group 5-aminopentyl, gr group 6aminohexyl, 2-methyl-3-aminopropyl group, 1,1-dimethyl-2-aminoethyl group, group 2 (methylamino) ethyl, group 3- (methylamino) propyl, group 4- (methylamino) butyl, group 5 (methylamino) ) pentyl, group 6- (methylamino) hexyl, group 2- (N-methyl-N-methoxycarbonylamino) ethyl, group 3- (N-methyl-N-methoxycarbonylamino) propyl, group 4 (N-methyl-N-methoxycarbonylamino) butyl, group 5- (N-methyl-Nmethoxycarbonylamino) pentyl, group 6- (N-methyl-N-methoxycarbonylamino) hexyl, group 2 (N-ethoxycarbonyl-N-methylamino) ethyl, group 3- (N-ethoxycarbonyl-N-methylamino ) propyl, group 4- (N-ethoxycarbonyl-N-methylamino) butyl, group 5- (N-ethoxycarbonyl-Nmethylamino) pentyl, group 6- (N-ethoxycarbonyl-N-methylamino) hexyl, group 2- [N-methyl -N (n-propoxycarbonylamino)] ethyl, group 3- [N-methyl-N- (n-propoxycarbonylamino)] propyl, group 4- [N-methyl-N- (n-propoxycarbonylamino)] butyl, group 5- [ N-methyl-N- (npropoxycarbonylamino)] pentyl, group 6- [N-methyl-N- (n-propoxycarbonylamino)] hexyl, group 2- [N- (ter-butoxycarbonyl) -N-methylamino)] ethyl, group 3- [N- (ter-butoxycarbonyl) -Nmethylamino)] propyl, group 4- [N- (ter-butoxycarbonyl) -N-methylamino)] butyl, group 5- [N (ter-butoxycarbonyl) -N-methylamino)] pentyl , group 6- [N- (tert-butoxycarbonyl) -Nmethylamino)] hexyl, group 2- [N-methyl-N- (n-pentoxicarbonyl) amino] ethyl, group 2- [Nmethyl-N- (n-hexyloxycarbonyl) amino] ethyl, group 2- (N-methylanilino) ethyl, group 3- (N-methylanilino) propyl, group 4- (N-methylanilino) butyl, group 2- (N-methyl-4Petition 870190039560, from 26/04/2019, p. 194/876

186/854

chloroanilino) ethyl, group 3- (N-methyl-4-chloroanilino) propyl, group 4- (N-methyl-4- chloroanilino) butyl, group 2- (4-fluoro-N-methylanilino) ethyl, group 3- (4-fluoro-N- methylanilino) propyl, group 2- (3-fluoro-N-methylanilino) ethyl, group 3- (3-fluoro-N- methylanilino) propyl, group 4- (3-fluoro-N-methylanilino) butyl, group 2- (2-fluoro-N- methylanilino) ethyl, group 3- (2-fluoro-N-methylanilino) propyl, group 4- (2-fluoro-N- methylanilino) butyl, group 2- (2-chloro-N-methylanilino) ethyl, group 3- (2-chloro-N- methylanilino) propyl, group 4- (2-chloro-N-methylanilino) butyl, group 2- (3-chloro-N- methylanilino) ethyl, group 3- (3-chloro-N-methylanilino) propyl, group 4- (3-chloro-N- methylanilino) butyl, group 2- (4-trifluoromethyl-N-methylanilino) ethyl, group 2- (4-

2- (3,5-ditrifluoromethyl-N-ethoxycarbonylanilino) ethyl group, 2-methylanilino) ethyl group, (3,5-ditrifluoromethyl-N-methylanilino) ethyl group, 2- (2,4-dimethyl-N-methylanilino) ethyl group, group 2- (3,5-dimethoxy-N-methylanilino) ethyl, group 2- (2,4,6-trimethylanilino) ethyl, group 2- (3,4,5-trimethoxyanilino) ethyl, group 3- (4-trifluoromethyl- N-methylanilino) propyl, group 4- (4-trifluoromethyl-N-methylanilino) butyl, group 2- (3-trifluoromethyl-N-methylanilino) ethyl, group

3- (3-trifluoromethyl-N-methylanilino) propyl, group 2- (2-trifluoromethyl-N-methylanilino) ethyl, group 3- (2-trifluoromethyl-N-methylanilino) propyl, group 4- (2-trifluoromethyl-Nmethylanilino ) butyl, group 2- (4-trifluoromethoxy-N-methylanilino) ethyl, group 3- (4-trifluoromethoxy-N-methylanilino) propyl, group 4- (4-trifluoromethoxy-N-methylanilino) butyl, group 2- (3-trifluoromethoxy -N-methylanilino) ethyl, group 3- (3-trifluoromethoxy-Nmethylanilino) propyl, group 4- (3-trifluoromethoxy-N-methylanilino) butyl, group 2- (2trifluoromethoxy-N-methylanilino) ethyl, group 3- (2 -trifluoromethoxy-N-methylanilino) propyl, group 4- (2-trifluoromethoxy-N-methylanilino) butyl, group 2- (4-methoxy-N-methylanilino) ethyl, group 3- (4-methoxy-N-methylanilino) propyl , 4- (4-methoxy-N-methylanilino) butyl group, 2- (3-methoxy-N-methylanilino) ethyl group, 3- (3-methoxy-N-methylanilino) propyl group, group

4- (3-methoxy-N-methylanilino) butyl, group 2- (2-methoxy-N-methylanilino) ethyl, group 3- (2-methoxy-N-methylanilino) propyl, group 4- (2-methoxy-N-methylanilino) ) butyl or similar. [0266] Examples of a phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, a phenoxy group (which can be substituted on the phenyl ring by at least one selected group) of a group consisting of a halogen atom, group

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187/854 C1-6 alkyl unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) and a C1-6 alkoxycarbonyl group) include a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably from 1 to 3 groups selected from a group consisting of a halogen atom, a phenoxy group (which can be substituted on the phenyl ring by 1 to 5, preferably from 1 to 3 groups selected from a group that consists of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) and a C1-6 alkoxycarbonyl group), for example, a phenyl group, group 2- fluorophenyl, group 3-fluorophenyl, group 4fluorophenyl, group 2-chlorophenyl, group 3-chlorophenyl, group 4-chlorophenyl, group 2bromophenyl, group 3-bromophenyl, group 4-bromophenyl, group 2-iodophenyl, group 3iodophenyl, group 4-iodophenyl , 2,3-difluorophenyl group, 3,4-difluorophenyl group, group

3.5- difluorophenyl, 2,4-difluorophenyl group, 2,6-difluorophenyl group, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group , 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl group, group

3.4.5- trichlorophenyl, group 2,4,6-trifluorophenyl, group 2,3,4,5,6-pentafluorophenyl, group

2.4.6- trichlorophenyl, group 2-fluoro-4-chlorophenyl, group 2-fluoro-4-bromophenyl, group 3fluoro-4-chlorophenyl, group 2-methoxycarbonylphenyl, group 3-methoxycarbonylphenyl, group 4-methoxycarbonylphenyl, group 2.4 -dimethoxycarbonylphenyl, 2,4,6-trimethoxycarbonylphenyl group, 2-ethoxycarbonylphenyl group, 3-ethoxycarbonylphenyl group, 4-ethoxycarbonylphenyl group, 2-propoxycarbonylphenyl group, 3-propoxycarbonylphenyl group, 4-propoxycarbonylphenyl group, 3-propoxycarbonylphenyl group, group 4-propoxycarbonylphenyl group. -butoxycarbonylphenyl, group 4-pentoxycarbonylphenyl, group 4-hexyloxycarbonylphenyl, group 2-phenoxyphenyl, group 3-phenoxyphenyl, group 4-phenoxyphenyl, group 2- (2-chlorophenoxy) phenyl, group 2- (3-chlorophenoxy) phenyl, group 2- (3 4chlorophenoxy) phenyl, group 3- (2-chlorophenoxy) phenyl, group 3- (3-chlorophenoxy) phenyl, group 3 (4-chlorophenoxy) phenyl, group 4- (2-chlorophenoxy) phenyl, group 4- (2,4 -dichlorophenoxy) phenyl, group 4- (2,4,6-trichlorophenoxy) phenyl, group 4- (3-chlorophenoxy) phenyl, gr upo 4- (4-chlorophenoxy) phenyl, group 2- (2-trifluoromethylphenoxy) phenyl, group 2- (3-trifluoromethylphenoxy) phenyl, group 2- (4-trifluoromethylphenoxy) phenyl, group 3- (2-

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188/854 trifluoromethylphenoxy) phenyl, group 3- (2-methylphenoxy) phenyl, group 3- (2,4dimethylphenoxy) phenyl, group 3- (2,4,6-trimethylphenoxy) phenyl, group 3- (2-methoxyphenoxy) phenyl , group 3- (2,4-dimethoxyphenoxy) phenyl, group 3- (2,4,6-trimethoxyphenoxy) phenyl, group 2- (3,5-

ditrifluoromethylphenoxy) phenyl, group 2- (3,5-ditrifluoromethoxyphenoxy) phenyl, group 3- (3- trifluoromethylphenoxy) phenyl, group 3- (4-trifluoromethylphenoxy) phenyl, group 4- (2- trifluoromethylphenoxy) phenyl, group 4- (3-trifluoromethylphenoxy) phenyl, group 4- (4- trifluoromethylphenoxy) phenyl, group 2- (2-trifluoromethoxyphenoxy) phenyl, group 2- (3- trifluoromethoxyphenoxy) phenyl, group 2- (4-trifluoromethoxyphenoxy) phenyl, group 3- (2- trifluoromethoxyphenoxy) phenyl, group 3- (3-trifluoromethoxyphenoxy) phenyl, group 3- (4- trifluoromethoxyphenoxy) phenyl, group 4- (2-trifluoromethoxyphenoxy) phenyl, group 4- (3-

trifluoromethoxyphenoxy) phenyl, group 4- (4-trifluoromethoxyphenoxy) phenyl or the like.

[0267] A C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1 alkoxy group -6 unsubstituted or substituted by halogen) includes a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), for example, a benzyloxycarbonyl group, 1-phenethyloxycarbonyl group, 2-phenethyloxycarbonyl group, 3-phenylpropoxycarbonyl group, 2-phenylpropoxycarbonyl group , 4-phenylbutoxycarbonyl group,

5-phenylpentyloxycarbonyl group, 4-phenylpentyloxycarbonyl group, group 6- phenylexyloxycarbonyl, group 2-fluorobenzyloxycarbonyl, group 3- fluorobenzyloxycarbonyl, group 4-fluorobenzyloxycarbonyl, group 2- chlorobenzyloxycarbonyl, group 3-chlorobenzyloxycarbonyl, group 4- chlorobenzyloxycarbonyl, group 2-bromobenzyloxycarbonyl, group 3- bromobenzyloxycarbonyl, group 4-bromobenzyloxycarbonyl, group 2- iodobenzyloxycarbonyl, group 3-iodobenzyloxycarbonyl, group 4- iodobenzyloxycarbonyl, group 2,3-difluorobenzyloxycarbonyl, group 3.4- difluorobenzyloxycarbonyl, group 3,5-difluorobenzyloxycarbonyl, group 2.4-

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189/854 difluorobenzyloxycarbonyl, group 2,6-difluorobenzyloxycarbonyl, group 2,4,6trifluorobenzyloxycarbonyl, group 2,3,4,5,6-pentafluorobenzyloxycarbonyl, group 3,4,5trifluorobenzyloxycarbonyl, dichlorobenzyloxycarbonyl, dichlorobyloxycarbonyl, dichlorobyloxycarbonyl, trichlorobicarbonyl trimethylbenzyloxycarbonyl, dimethoxybenzyloxycarbonyl, group group group group group group group group group group group group

3.4-

2.4-

2,4,62,3- dichlorobenzyloxycarbonyl,

3,5-dichlorobenzyloxycarbonyl,

2,6-dichlorobenzyloxycarbonyl,

3,4,5-trichlorobenzyloxycarbonyl,

2- difluoromethylbenzyloxycarbonyl, group

3,5-dimethylbenzyloxycarbonyl,

3- methoxybenzyloxycarbonyl,

2,4,6-trimethoxybenzyloxycarbonyl, group group group group

32,4,63,53difluoromethylbenzyloxycarbonyl, 4-difluoromethylbenzyloxycarbonyl group, 4-chloro3-difluoromethylbenzyloxycarbonyl group, 3-chloro-4-difluoromethylbenzyloxycarbonyl, 3bromo-4-difluoromethylbenzyloxycarbonyl group, group 3trifluorometilbenziloxicarbonila group, 4trifluorometilbenziloxicarbonila group, 4-fluoro-3trifluorometilbenziloxicarbonila group, 3-fluoro-4trifluorometilbenziloxicarbonila group, 4-chloro-3-pentafluoroetilbenziloxicarbonila group, 3-chloro-4-pentafluoroetilbenziloxicarbonila group, 2pentafluoroetilbenziloxicarbonila group, 3-pentafluoroetilbenziloxicarbonila, grupo4pentafluoroetilbenziloxicarbonila group, 2-trifluoromethoxybenzyloxycarbonyl, group3trifluoromethoxybenzyloxycarbonyl, group 4-trifluoromethoxybenzyloxycarbonyl, group4fluoro-3-trifluoromethoxybenzyloxycarbonyl, group 3-fluoro-4trifluoromethoxybenzyloxycarbonyl, group 2-p 3pentafluoroethoxybenzyloxycarbonyl group, 4-pentafluoroethoxybenzyloxycarbonyl group, 3-chloro-4-trifluoromethoxybenzyloxycarbonyl group, 3-chloro-4pentafluoroethoxybenzyloxycarbonyl group, group 2- (2-trifluoromethylphenyl) etoxicarbonyl group

2- (3-trifluoromethylphenyl) ethoxycarbonyl, group 2- (4-trifluoromethylphenyl) ethoxycarbonyl, group (2-trifluoromethoxyphenyl) methoxycarbonyl, group (3trifluoromethoxyphenyl) methoxycarbonyl, group 2- (4-trifluoromethoxyphenylphenylphenylphenyl) group ) ethoxycarbonyl, group 2- (3Petition 870190039560, of 26/04/2019, page 198/876

190/854 pentafluoroethoxyphenyl) ethoxycarbonyl, group 2- (4-pentafluoroethoxyphenyl) ethoxycarbonyl, group 3- (2-trifluoromethylphenyl) propoxycarbonyl, group3- (3tnfluoromethylphenyl) propoxycarbonyl, group 3- (4-trifluoromethyl) trifluoromethylphenyl) propoxycarbonyl, group 3- (3-trifluoromethoxyphenyl) propoxycarbonyl, group 3- (4-trifluoromethoxyphenyl) propoxycarbonyl, group 3- (3-pentafluoroethoxyphenyl) propoxycarbonyl, group 3- (4pentafluorooxyphenyl), propoxycarbonyl group (5- 4-trifluoromethylphenyl) pentyloxycarbonyl, group 4- (4-trifluoromethylphenyl) pentyloxycarbonyl, group4- (4trifluoromethoxyphenyl) pentyloxycarbonyl, group 6- (3-trifluoromethylphenyl) hexyloxycarbonyl, group 6- (4-trifluoromethyl) hexyl similar.

[0268] A C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, cyano group, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) includes a phenyl C1-6 alkoxycarbonyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of an atom halogen, cyano group, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), for example, a benzyloxycarbonyl group, phenylethoxycarbonyl group, 3-phenylpropoxycarbonyl group, 2-phenylpropoxycarbonyl group , group 4-phenylbutoxycarbonyl, group 5-phenylpentoxicarbonyl, group 4-phenylpentoxicarbonyl, group 6-phenylexyloxycarbonyl, group 2-fluorobenzyloxycarbonyl, group 3-fluorobenzyloxycarbonyl, group 4fluorobenzyloxycarbonyl, group 2- (2-fluorophenyl) ethoxycarbonyl, group 1- (3fluorophenyl) ethoxycarbonyl, group 2- (4-fluorophenyl) ethoxycarbonyl, group 2chlorobenzyloxycarbonyl, group 3-chlorobenzyloxycarbonyl, group 4chlorobenzyloxycarbonyl, group 2chlorobenzyloxycarbonyl , group 1- (3-chlorophenyl) ethoxycarbonyl, group 2- (4-iodophenyl) ethoxycarbonyl, group 2- (2,3dichlorophenyl) ethoxycarbonyl, group (2,4,6-trichlorophenyl) methoxycarbonyl, group (2,3,4,5 , 6Petition 870190039560, of 26/04/2019, p. 199/876

191/854 group group group group group group 2-cyanobenzyloxycarbonyl, group 4-cyanobenzyloxycarbonyl, group

3.4.5- tricianobenzyloxycarbonyl, group

3-cyanophenylethoxycarbonyl, 2-methylbenzyloxycarbonyl,

2.4.6- trimethylbenzyloxycarbonyl, group group group

32,4242,42pentafluorofenil) metoxicarbonila, cianobenziloxicarbonila, dicianobenziloxicarbonila, cianofeniletoxicarbonila, cianofeniletoxicarbonila, dimetilbenziloxicarbonila, trifluorometilbenziloxicarbonila, 3-trifluorometilbenziloxicarbonila group 4trifluorometilbenziloxicarbonila group dimetoxibenziloxicarbonila, 2,4,6-tnmetoxibenziloxicarbonila group trifluorometoxibenziloxicarbonila group, 3-trifluorometoxibenziloxicarbonila, 4trifluorometoxibenziloxicarbonila group, group 2- (2-trifluoromethylphenyl) ethoxycarbonyl, group 2 (3-trifluoromethylphenyl) ethoxycarbonyl, group 2- (4-trifluoromethylphenyl) ethoxycarbonyl, group 2- (2-trifluoromethoxyphenyl) ethoxycarbonyl, group 2- (3-trifluoromethylphenethoxycarbonyl, group 2- (3-trifluoromethylphenoxycarbonyl) group 2- 2- (4-trifluoromethoxyphenyl) ethoxycarbonyl, group 3- (2trifluoromethylphenyl) propoxycarbonyl, group 3- (3-trifluoromethylphenyl) propoxycarbonyl, group 3- (4-trifluoromethylphenyl) propoxycarbonyl, group 3- (2trifluoromethoxyphenyl), group 3- -trifluoromethoxyphenyl) pro poxycarbonyl, group 3- (4-trifluoromethoxyphenyl) propoxycarbonyl, group 3- (4-biphenylyl) propoxycarbonyl, group 4- (4-biphenylyl) butoxycarbonyl, group 5- (4-biphenylyl) pentoxycarbonyl, group 4- (3trifluoromethylphenyl) butoxycarbonyl group 5- (4-trifluoromethylphenyl) pentyloxycarbonyl, group 4- (4-trifluoromethylphenyl) pentoxycarbonyl, group 4- (4trifluoromethoxylphenyl) pentoxycarbonyl, group 6- (3-trifluoromethylphenyl) hexyloxycarbonyl, group 6- (4-triphenyl) - (4trifluoromethoxyphenyl) hexyloxycarbonyl or similar.

[0269] A phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom and an unsubstituted or substituted halogen C1-6 alkyl group) is one phenyl C 1-6 alkyl group unsubstituted or substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom and a C 1-6 alkyl group unsubstituted or substituted by halogen , with group 2-methoxybenzyloxycarbonyl, group 2,42,4,6-trimethoxybenzyloxycarbonyl, group 2group

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Examples of the same include a benzyl group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 4-phenylpentyl group, 6-phenylexyl group , 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group, 2-iodobenzyl group, 2-iodobenzyl group 3-iodobenzyl, group 4-iodobenzyl, group 2,3difluorobenzyl, group 3,4-difluorobenzyl, group 3,5-difluorobenzyl, group 2,4difluorobenzyl, group 2,6-difluorobenzyl, group 2,3,4,5,6 -pentafluorobenzyl, group 2,3-dichlorobenzyl, group 3,4-dichlorobenzyl, group 3,5-dichlorobenzyl, group 2,4dichlorobenzyl, group 2,6-dichlorobenzyl, group 2-trifluoromethyl benzyl, group 3trifluoromethyl benzyl, group 4-trifluoryl , 2-methylbenzyl group, 2,3dimethylbenzyl group, 2,4,6-trimethylbenzyl group, 3,5-ditrifluoromethylbenzyl group, group 2- (2-

trifluoromethylphenyl) ethyl, group 2- (3-trifluoromethylphenyl) ethyl, group 2- (4- trifluoromethylphenyl) ethyl, group 3- (2-trifluoromethylphenyl) propyl, group 3- (3- trifluoromethylphenyl) propyl, group 3- (4-trifluoromethylphenyl) propyl, group 3- (2- trifluoromethylphenyl) propyl, group 5- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethylphenyl) pentyl, group 6- (3-trifluoromethylphenyl) hexyl, group 6- (4-

trifluoromethylphenyl) hexyl or the like.

[0270] A C1-6 alkyl piperidinyl group (which can be substituted on the piperidine ring by at least one phenoxy group (which can have at least one unsubstituted C1-6 alkyl group or substituted by halogen on the phenyl ring as a substituent) as a substituent) includes a C1-6 alkyl piperidinyl group (which may be substituted on the piperidine ring by at least one phenoxy group (which may have from 1 to 5, preferably from 1 to 3 C1-6 alkyl groups unsubstituted or substituted by halogen in the phenyl ring as a substituent) as a substituent), for example, piperidin-1-ylmethyl group, piperidin-2-ylethyl group, piperidin-3-ylpropyl group, piperidin4-ylbutyl group, piperidin-1-ilpentyl group, group piperidin-2-yl-n-hexyl, group 4-

phenoxypiperidin-1-ylmethyl, group 2- (4-phenoxypiperidin-1-yl) ethyl, group 3- (4- phenoxypiperidin-1-i) propyl, group 4- (4-phenoxypiperidin-1-yl) butyl, group 5- (4- phenoxypiperidin-1-i) pentyl, group 6- (4-phenoxypiperidin-1-yl) hexyl, group 4- (3-

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193/854 methylphenoxy) piperidin-1-ylmethyl, group 4- (2,5-dimethylphenoxy) piperidin-1-ylmethyl, group 4 (2,4,6-trimethylphenoxy) pipendin-1-ylmethyl, group 4- (3, 5-ditrifluoromethylphenoxy) pipendin-1 ylmethyl, group 4- (2-trifluoromethylphenoxy) pipendin-1-ylmethyl, group 2- [4- (2trifluoromethylphenoxy) pipendin-1-yl] ethyl, group 3- [4- (2- trifluoromethylphenoxy) pipendin-1 yl] propyl, group 4- [4- (2-trifluoromethylphenoxy) piperidin-1 -yl] butyl, group 5- [4- (2trifluoromethylphenoxy) pipendin-1 -yl] pentiIa, group 6- [4 - (2-trifluoromethylphenoxy) pipendin-1 yl] hexyl, group 4- (3-trifluoromethylphenoxy) pipendin-1-ylmethyl, group 2- [4- (3trifluoromethylphenoxy) pipendin-1 -yl] ethyl, group 3- [4 - (3-trifluoromethylphenoxy) pipendin-1 yl] propyl, group 4- [4- (3-trifluoromethylphenoxy) piperidin-1 -yl] butyl, group 5- [4- (3trifluoromethylphenoxy) pipendin-1-yl] pentyl, group 6- [4- (3-trifluoromethylphenoxy) pipendin-1 yl] hexyl, group 4- (4-trifluoromethylphenoxy) pipendin-1-ylmethyl, group 2- [4- (4trifluoromethylphenoxy) pipendin -1 -il] ethyl, group 3- [4- (4-trifluoromethylphenoxy) pipendin-1 yl] propyl, group 4- [4- (4-trifluoromethylphenoxy) piperidin-1 -yl] butyl, group 5- [4 - (4trifluoromethylphenoxy) pipendin-1-yl] pentyl, group 6- [4- (4-trifluoromethylphenoxy) pipendin-1yl] hexyl or the like.

[0271] A phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom; a C1-6 alkyl group unsubstituted or substituted by halogen; a C1-6 alkoxy group unsubstituted or substituted by halogen; an amino group which may have a group selected from a group consisting of a C1-6 alkyl group and a phenyl C1-6 alkyl group (which may be substituted on the phenyl ring by at least one selected group a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent; a phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by a C1-6 alkoxy phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, unsubstituted C1-6 alkyl group or substituted by halogen and C1 alkoxy group -6 not replaced

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194/854 or replaced with halogen); and a piperidyl group (which can have at least one amino group on the piperidine ring which can have at least one group selected from a group consisting of a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) and C1-6 alkyl group)) includes a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom; an unsubstituted or substituted C 1-6 alkyl group; a C1-6 alkoxy group unsubstituted or substituted by halogen; an amino group that can have 1 to 2 groups selected from a group consisting of a C1-6 alkyl group and a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom; C1-6 alkyl group unsubstituted or substituted by halogen; and C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent; a phenoxy group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and alkoxy group Ci-6 not substituted or substituted by halogen); a C1-6 alkoxy phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, unsubstituted or substituted C 1 -C 6 alkyl group and C1-6 alkoxy group not substituted or substituted by halogen); and a piperidyl group (which can have at least one amino group on the piperidine ring which can have 1 to 2 groups selected from a group consisting of a phenyl C 1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) and C1-6 alkyl group e)), for example, a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, group

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195/854

2-bromophenyl, group 3-bromophenyl, group 4-bromophenyl, group 2-iodophenyl, group 3iodophenyl, group 4-iodophenyl, group 2,3-difluorophenyl, group 3,4-difluorophenyl, group

3.5- difluorophenyl, 2,4-difluorophenyl group, 2,6-difluorophenyl group, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group , 3,4,5-trifluorophenyl group, 3,4,5-trichlorophenyl group, group

2,4,6-trifluorophenyl, group 2,3,4,5,6-pentafluorophenyl, group 2,4,6-trichlorophenyl, group 2-methylphenyl, group 3-methylphenyl, group 4-methylphenyl, group 2,4- dimethylphenyl group

3.4.5- trimethylphenyl, 3,5-ditrifluoromethylphenyl group, 2-methyl-3-chlorophenyl group, 3methyl-4-chlorophenyl group, 2-chloro-4-methylphenyl group, 2-methyl-3-fluorophenyl group, 2trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2pentafluoroethylphenyl group, 3-pentafluoroethylphenyl group, 4-pentafluoroethylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 3-isopropyl group, 3-isopropyl group butylphenyl, group 4-ter-butylphenyl, group 2-sec-butylphenyl, group 3-secbutylphenyl, group 4-sec-butylphenyl, group 2-n-heptafluoropropylphenyl, group 3-nheptafluoropropylphenyl, group 4-n-heptafluoropropylen, group 4 pentylphenyl, 4hexylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2methoxy-3-chlorophenyl group, 2-fluoro-3-methoxyphenyl group, 2-fluoro-4-methoxyphenyl group, group 2,6- dimethoxyphenyl, 2,4,6-trimethoxyphenyl group, 3,5-dirifluoromethoxyphenyl group, 2-trifluoromethoxyphenyl group , 3-trifluoromethoxyphenyl group, 4trifluoromethoxyphenyl group, 2-pentafluoroethoxyphenyl group, 3-pentafluoroethoxyphenyl group, 4-pentafluoroethoxyphenyl group, 2-isopropoxyphenyl group, 3-isopropoxyphenyl group, 4-isopropoxyphenyl group, 3-isopropoxyphenyl group -butoxyphenyl, group 4-terbutoxyphenyl, group 2-sec-butoxyphenyl, group 3-sec-butoxyphenyl, group 4-secbutoxyphenyl, group 2-n-heptafluoropropoxyphenyl, group 3-n-heptafluoropropoxyphenyl, group 4-n-heptafloropropoxypropyl -pentyloxyphenyl, group 4-hexyloxyphenyl, group 3-aminophenyl, group 3-methylaminophenyl, group 3-dimethylaminophenyl, group 4methylaminophenyl, group 4-dimethylaminophenyl, group 4-ethylaminophenyl, group 4diethylaminophenyl, group 4-n-propyl, group 4-n-propyl -n-propylaminophenyl, 4n-butylaminophenyl group, 4-di-n-butylaminophenyl group, 4-n-pentylaminophenyl group, 4di-n-pentylaminophenyl group, 4-n-hexylaminophenyl group, 4-di-n-hexylaminophenyl group,

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196/854 group 4-benzylaminophenyl, group 4- (2-fluorobenzylamino) phenyl, group 4- (3-

fluorobenzylamino) phenyl, group 4- (4-fluorobenzylamino) phenyl, group 4- (2,3- difluorobenzylamino) phenyl, group 4- (2,4-difluorobenzylamino) phenyl, group 4- (3,4- difluorobenzylamino) phenyl, group 4- (3,5-difluorobenzylamino) phenyl, group 4- (2- chlorobenzylamino) phenyl, group 4- (3-chlorobenzylamino) phenyl, group 4- (4- chlorobenzylamino) phenyl, group 4- (2-bromobenzylamino) phenyl, group 4- (3- bromobenzylamino) phenyl, group 4- (4-bromobenzylamino) phenyl, group 4- (2,3- dichlorobenzylamino) phenyl, group 4- (2,4-dichlorobenzylamino) phenyl, group 4- (3,4- dichlorobenzylamino) phenyl, group 4- (3,5-dichlorobenzylamino) phenyl, group 4- (2- methylbenzylamino) phenyl, group 4- (3-methylbenzylamino) phenyl, group 4- (4- methylbenzylamino) phenyl, group 4- (2-ethylbenzylamino) phenyl, group 4- (3- ethylbenzylamino) phenyl, group 4- (4-ethylbenzylamino) phenyl, group 4- (4-n- propylbenzylamino) phenyl, group 4- (4-ter-butylbenzylamino) phenyl, group 4- (4-n- butylbenzylamino) phenyl, group 4- (2-trifluoromethylbenzylamino) phenyl, group 4- (3-

trifluoromethylbenzylamino) phenyl, group 4- (4-trifluoromethylbenzylamino) phenyl, group 4- (2pentafluoroethylbenzylamino) phenyl, group 4- (3-pentafluoroethylbenzylamino) phenyl, group 4- (2,3-dimethylbenzylamino) phenyl, group 4- (3 4,5-trimethylbenzylamino) phenyl, group 4- (4pentylbenzylamino) phenyl, group 4- (4-hexylbenzylamino) phenyl, group 4- (3methoxybenzylamino) phenyl, group 4- (3,5-dimethoxybenzylamino) phenyl, group 4- ( 2,4,6trimethoxybenzylamino) phenyl, group 4- (2-trifluoromethoxybenzylamino) phenyl, group 4- (3-trifluoromethoxybenzylamino) phenyl, group 4- (2-pentafluoroethoxybenzylamino) phenyl, group 4- ( 3pentafluoroethoxybenzylamino) phenyl, group 4- (4-pentafluoroethoxybenzylamino) phenyl, group (phenethylamino) phenyl, group 4- (2-fluorophenethylamino) phenyl, group 4- (3-

fluorophenethylamino) phenyl, group 4- (4-fluorophenethylamino) phenyl, group 4- (2,3- difluorophenethylamino) phenyl, group 4- (2,4-difluorophenethylamino) phenyl, group 4- (3,4- difluorophenethylamino) phenyl, group 4- (3,5-difluorophenethylamino) phenyl group 4- (2- chlorophenethylamino) phenyl, group 4- (3-chlorophenethylamino) phenyl, group 4- (4- chlorophenethylamino) phenyl, group 4- (2-bromophenethylamino) phenyl, group 4- (3- bromophenethylamino) phenyl, group 4- (4-bromophenethylamino) phenyl, group 4- (2,3-

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197/854

dichlorophenethylamino) phenyl, group 4- (2,4-dichlorophenethylamino) phenyl, group 4- (3,4- dichlorophenethylamino) phenyl, group 4- (3,5-dichlorophenethylamino) phenyl, group 4- (2- methylphenethylamino) phenyl, group 4- (3-methylphenethylamino) phenyl, group 4- (4- methylphenethylamino) phenyl, group 4- (4-ethylphenethylamino) phenyl, group 4- (4- propylphenethylamino) phenyl, group 4- (4-ter-butylphenethylamino) phenyl, group 4- (2-

trifluoromethylphenethylamino) phenyl, group 4- (3-trifluoromethylphenethylamino) phenyl, group 4 (4-trifluoromethylphenethylamino) phenyl, group 4- (2-pentafluoroethylphenethylamino) phenyl, group 4- (3-pentafluoroethylphenyl), group 4- -dimethylphenethylamino) phenyl, group 4- (2-trifluoromethoxyphenethylamino) phenyl, group 4- (3-trifluoromethoxyphenethylamino) phenyl, group 4- (4-trifluoromethoxyphenethylamino) phenyl, group 4- (2pentafluoroethoxyphenylamino-group 4-) phenyl ) phenyl, group 4- (4-pentafluoroethoxyphenethylamino) phenyl, group 4- (3-phenylpropylamino) phenyl, group 4- [3- (2-fluorophenyl) propylamino] phenyl, group 4- [3- (3fluorophenyl) propylamino] phenyl , group 4- [3- (4-fluorophenyl) propylamino] phenyl, group 4- [3 (2,3-difluorophenyl) propylamino] phenyl, group 4- [3- (2,4-difluorophenyl) propylamino] phenyl, group 4- [3- (3,4-difluorophenyl) propylamino] phenyl, group 4- [3- (3,5difluorophenyl) propylamino] phenyl, group 4- [3- (2-chlorophenyl) propylamino] phenyl, group 4- [ 3 (3-chlorophenyl) propylamino] phen ila, group 4- [3- (4-chlorophenyl) propylamino] phenyl, group 4- [3 (2-bromophenyl) propylamino] phenyl, group 4- [3- (3-bromophenyl) propylamino] phenyl, group 4 [3 - (4-bromophenyl) propylamino] phenyl, group 4- [3- (2,3-dichlorophenyl) propylamino] phenyl, group 4- [3- (2,4-dichlorophenyl) propylamino] phenyl, group 4- [3- (3,4dichlorophenyl) propylamino] phenyl, group 4- [3- (3,5-dichlorophenyl) propylamino] phenyl, group 4 [3- (2-methylphenyl) propylamino] phenyl, group 4- [3- (3-methylphenyl ) propylamino] phenyl, group 4 [3- (4-methylphenyl) propylamino] phenyl, group 4- [3- (2-ethylphenyl) propylamino] phenyl, group 4- [3 (3-ethylphenyl) propylamino] phenyl, group 4 - [3- (4-ethylphenyl) propylamino] phenyl, group 4- [3- (4propylphenyl) propylamino] phenyl, group 4- [3- (4-ter-butylphenyl) propylamino] phenyl, group 4- [3 (4 -butylphenyl) propylamino] phenyl, group 4- [3- (2-trifluoromethylphenyl) propylamino] phenyl, group 4- [3- (3-trifluoromethylphenyl) propylamino] phenyl, group 4- [3- (4trifluoromethylphenyl) propylamino] phenyl, group 4- [3- (2pentafluoroethylphenyl) propylamino] phenyl, group 4- [3- (3

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198/854 pentafluoroethylphenyl) propylamino] phenyl, group 4- [3- (2,3-dimethylphenyl) propylamino] phenyl, group 4- [3- (3,4,5-timetylphenyl) propylamino] phenyl, group 4- [3 - (4pentylphenyl) propylamino] phenyl, group 4- [3- (4 trifluoromethoxyphenyl) propylamino] phenyl, trifluoromethoxyphenyl) propylamino] phenyl, pentafluoroethoxyphenylphenyl] propylamino] propylamino] phenyl, propylamino] phenyl, gi group 4-phenoxyphenyl, group 2- (2-chlorophenoxes hexylphenyl) propylamino] phenyl, group 4- [3- (2group 4- [3group 4- [3- (4group 4- [3- (2group 4- [ 3- (3-group 4- [3- (4-group 2-phenoxyphenyl, group 3-phenoxyphenyl,) phenyl, group 2- (3-chlorophenoxy) phenyl, group

2- (4-chlorophenoxy) phenyl, group 3- (2-chlorophenoxy) phenyl, group 3- (3-chlorophenoxy) phenyl, group 3- (4-chlorophenoxy) phenyl, group 4- (2-chlorophenoxy) phenyl, group 4- (3-chlorophenoxy) phenyl, group 4- (4-chlorophenoxy) phenyl, group 3- (4-methylphenoxy) phenyl, group 3-

(3,4-dimethylphenoxy) phenyl, group 4- (2,4,6-trimethylphenoxy) phenyl, group 2- (2- trifluoromethylphenoxy) phenyl, group 2- (3-trifluoromethylphenoxy) phenyl, group 2- (4- trifluoromethylphenoxy) phenyl, group 3- (2-trifluoromethylphenoxy) phenyl, group 3- (3- trifluoromethylphenoxy) phenyl, group 3- (4-trifluoromethylphenoxy) phenyl, group 4- (2- trifluoromethylphenoxy) phenyl, group 4- (3-trifluoromethylphenoxy) phenyl, group 4- (4- trifluoromethylphenoxy) phenyl, group 3- (4-methoxyphenoxy) phenyl, group 2- (3,4- dimethoxyphenoxy) phenyl, group 4- (2,4,6-trimethoxyphenoxy) phenyl, group 2- (2- trifluoromethoxyphenoxy) phenyl, group 2- (3-trifluoromethoxyphenoxy) phenyl, group 2- (4- trifluoromethoxyphenoxy) phenyl, group 3- (2-trifluoromethoxyphenoxy) phenyl, group 3- (3- trifluoromethoxyphenoxy) phenyl, group 3- (4-trifluoromethoxyphenoxy) phenyl, group 4- (2- trifluoromethoxyphenoxy) phenyl, group 4- (3-trifluoromethoxyphenoxy) phenyl, group 4- (4- trifluoromethoxyphenoxy) phenyl, 4-benzyloxyphenyl group, 4- (2-phenylethoxy) phenyl group, group

4- (3-phenylpropoxy) phenyl, group 4- (4-phenylbutoxy) phenyl, group 4- (5-phenylpentoxy) phenyl, group 4- (6-phenylexyloxy) phenyl, group 4- (4-fluorobenzyloxy) phenyl, group 4- (3-fluorobenzyloxy) phenyl, group 4- (2-fluorobenzyloxy) phenyl, group 4- (4-chlorobenzyloxy) phenyl, group 4- (3-chlorobenzyloxy) phenyl, group 4- (2-chlorobenzyloxy) phenyl, group 3- (4 -methylbenzyloxy) phenyl, group 2- (2,4-dimethylbenzyloxy) phenyl, group 4- (2,4,6Petition 870190039560, from 26/04/2019, page 207/876

199/854 group

4- (3-fluorophenyloxy) phenyl,

4- (4-chlorophenyloxy) phenyl,

4- (2-chlorophenyloxy) phenyl,

4- (3-trifluoromethylphenylhoxyl) phenyl, group group

4- (24- (34- (24- (4group group group trimethylbenzyloxy) phenyl, group 4- (2-trifluoromethylbenzyloxy) phenyl, group 4- (3trifluoromethylbenzyloxy) phenyl, group 4- (4-trifluoromethylbenzyloxy) phenyl, group 3 - (4methoxybenzyloxy) phenyl, group 2- (2,4-dimethoxybenzyloxy) phenyl, group 4- (2,4,6trimethoxybenzyloxy) phenyl, group 4- (2-trifluoromethoxybenzyloxy) phenyl, group 4- (3trifluoromethoxybenzyloxy) phenyl, group 4 - (4-trifluoromethoxybenzyloxy) phenyl, group 4- (4fluorophenyloxy) phenyl, fluorophenylethoxy) phenyl, chlorophenylethoxy) phenyl, trifluoromethylphenyloxy) phenyl, group trifluoromethylphenylhoxyl) phenyl, group 4- (2-trifluoroethyl) , group 4- (4-trifluoromethoxyphenylhoxyl) phenyl, group 4 (3-trifluoromethoxyphenylhoxyl) phenyl, group 4- (4-trifluoromethoxyphenylhoxyl) phenyl, group 4- [3- (4-fluorophenyl) propoxy] phenyl, group 4- [3 - (3-fluorophenyl) propoxy] phenyl, group 4- [3- (2-fluorophenyl) propoxy] phenyl, group 4- [3- (2-trifluoromethyl phenyl) propoxy] phenyl, group 4- [3- (3-trifluoromethylphenyl) propoxy] phenyl, group 4- [3- (4-trifluoromethylphenyl) propoxy] phenyl, group 4- [3- (2-trifluoromethylphenyl) propoxy] phenyl, group 4- [3- (3trifluoromethoxyphenyl) propoxy] phenyl, group 3- (4-trifluoromethoxyphenyl) propoxy] phenyl, group 4- [4- (3-trifluoromethylphenyl) butoxy] phenyl, group 4- [5- (4-trifluoromethylphenyl) pentoxy] phenyl, group 4- [4- (4-trifluoromethoxyphenyl) pentoxy] phenyl, group 4- [6- (3trifluoromethylphenyl) hexyloxy] phenyl, group 4- [6- (4-trifluoromethylphenyl) hexyloxy] phenyl, group 4- [6- (4-trifluoromethoxyphenyl) hexyloxy] phenyl, group 3- (piperidin-1-yl) phenyl, group 2- (4benzylaminopiperidin-1-yl) phenyl, group 2- (3-benzylaminopiperidin-1-yl) phenyl, group 2- (4-benzylaminopiperidin-1-yl) phenyl, group 2- (4-benzylaminopiperidin-1-yl) phenyl, group 2- (4-benzylaminopiperidin-1-yl) phenyl, group 2- [4- (4-chlorobenzyl) aminopiperidin -1-yl] phenyl, group 2- [2- (2,4-dichlorobenzyl) aminopiperidin-1-yl] phenyl, group 2- [4- (2,4,6trichlorobenzyl) aminopipendin-1 -yl] phenyl, group 2- [4- (4-methylbenzyl) aminopiperidin-1yl] phenyl, group 2- [4- (2,4-dimethylbenzyl) aminopiperidin-1 -yl] phenyl, group 2- [4- ( 2,4,6trimethylbenzyl) aminopipendin-1-yl] phenyl, trifluoromethylbenzyl) aminopipendin-1-yl] phenyl, di (trifluoromethyl) benzyl] piperidin-1 -yl} phenyl, group

2- [4- (42- {4- [2,42- {4- [2,4,6 group group

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200/854 tri (trifluoromethyl) benzyl] am inopiperidin-1 -yl} phenyl, group 2- [4- (4methoxybenzyl) aminopiperidin-1 -yl] phenyl, group 2- [4- (2,4 -dimethoxybenzyl) aminopyridin-1 yl] phenyl, group 2- [4- (2,4,6-trimethoxybenzyl) aminopiperidin-1-yl] phenyl, group 2- [4- (4trifluoromethoxybenzyl) aminopiperidin-1-yl] phenyl , 2- {4- [2,4,6tri (tnfluoromethoxy) benzyl] aminopipendin-1-yl} phenyl group, 2- {4- [3,5di (trifluoromethoxy) benzyl] aminopipendin-1-yl} phenyl group, group 4- (4-methylaminopiperidin-1-yl) phenyl, group 4- (4-dimethylaminopiperidin-1-yl) phenyl, group 4- (4-ethylaminopiperidin-1yl) phenyl, group 4- (4-diethylaminopiperidin-1-yl) ) phenyl, group 4- (4-n-propylaminopiperidinyl)

1-yl) phenyl, group 4- (4- (din-propylamino) piperidin-1-yl, group 4- (4-n-butylaminopiperidin-1-yl) phenyl, group 4- [4- (N-ethyl-N -methylamino) piperidin-1-yl] phenyl, group 4- [4- (N-benzyl-N-methylamino) piperidin-1-yl] phenyl, group 4- (4-npentylaminopiperidin-1-yl) phenyl, group 4- (4-n-hexylaminopiperidin-1-yl) phenyl or the like.

[0272] Examples of a C1-6 alkoxy biphenylyl group include 1,1'-biphenyl-4ylmethoxy group, 2- (1,1'-biphenyl-4-yl) ethoxy group, 3- (1,1'-biphenyl group) -4-yl) propoxy, group 4- (1, Tbiphenyl-4-yl) butoxy, group 5- (1,1'-biphenyl-4-yl) pentyloxy, group 6- (1,1'-biphenyl-4 -yl) hexyloxy or the like.

[0273] A C3-6 phenyl alkenyloxy group that can be substituted on the phenyl ring by at least one halogen atom includes a C3-6 phenyl alkenyloxy group that can be substituted on the phenyl ring by from 1 to 5, preferably from 1 to 5 3 halogen atoms, for example, a 3-phenyl-2-propenyloxy group (common name: cinnamoyl group), 4-phenyl-2-butenyloxy group, 4-phenyl-3-butenyloxy group, group 3- (2-fluorophenyl ) -2-propenyloxy, group 3- (3-fluorophenyl) -2-propenyloxy, group 3- (4-fluorophenyl) -2-propenyloxy, group 3 (2,3-difluorophenyl) -2-propenyloxy, group 3- ( 2,4-difluorophenyl) -2-propenyloxy, group 3- (3,4difluorophenyl) -2-propenyloxy, group 3- (3,5-difluorophenyl) -2-propenyloxy, group 3- (2chlorophenyl) -2-propenyloxy, group 3- (3-chlorophenyl) -2-propenyloxy, group 3- (4-chlorophenyl) -2propenyloxy, group 3- (2,4,6-trichlorophenyl) -2-propenyloxy, group 3- (2,3,4 , 5,6pentafluorophenyl) -2-propenyloxy, group 3- (2,3-dichlorophenyl) -2-propenyloxy, group 3- (2,4dichlorophenyl) -2-propenyloxy, group 3- ( 3,4-dichlorophenyl) -2-propenyloxy, group 3- (3,5dichlorophenyl) -2-propenyloxy, group 3- (2-bromophenyl) -2-propenyloxy, group 3- (3

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201/854 bromophenyl) -2-propenyloxy, group 3- (4-bromophenyl) -2-propenyloxy, group 4- (4-chlorophenyl) -

3-butenyloxy, group 4- (2,3-dichlorophenyl) -3-butenyloxy, group 4- (2,4-dichlorophenyl) -3butenyloxy, group 4- (3,4-dichlorophenyl) -3-butenyloxy, group 4- (3,5-dichlorophenyl) -3butenyloxy, group 5- (4-chlorophenyl) -4-pentenyloxy, group 5- (2,3-dichlorophenyl) -4-pentenyloxy, group 5- (2,4-dichlorophenyl) -4 -pentenyloxy, group 5- (3,4-dichlorophenyl) -4-pentenyloxy, group

5- (3,5-dichlorophenyl) -4-pentenyloxy, group 6- (4-chlorophenyl) -5-hexenyloxy, group 6- (2,3dichlorophenyl) -5-hexenyloxy, group 6- (2,4-dichlorophenyl) -5-hexenyloxy, group 6- (3,4-dichlorophenyl) -5-hexenyloxy, group 6- (3,5-dichlorophenyl) -5-hexenyloxy or the like.

[0274] A phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, cyano group, unsubstituted or substituted C1-6 alkyl group or halogen and C1- alkoxy group 6 unsubstituted or substituted by halogen) includes a phenoxy group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, cyano group, alkyl group C1-6 unsubstituted or substituted by halogen and alkoxy group C1-6 unsubstituted or substituted by halogen), for example, a phenoxy group, 2-fluorophenoxy group, group

3-fluorophenoxy, 4-fluorophenoxy group, 2-chlorophenoxy group, 3-chlorophenoxy group, 4-chlorophenoxy group, 2-bromophenoxy group, 3-bromophenoxy group, 4-bromophenoxy group, 2,3-dichlorophenoxy group, 3,4-dichlorophenoxy group , 2,4-dichlorophenoxy group, 3,4,5trichlorophenoxy group, 2,4,6-thchlorophenoxy group, 2,3,4,5,6-pentafluorophenoxy group, 2-cyanophenoxy group, 3-cyanophenoxy group, 4-cyanophenoxy group, 2-methylphenoxy group, 2,4,6tricianophenoxy, 2,3-dicytophenoxy group, 3-methylphenoxy group, 4-methylphenoxy group, group

2-ethylphenoxy, 3-ethylphenoxy group, 4-ethylphenoxy group, 4-n-propylphenoxy group, 4-terbuthylphenoxy group, 4-n-butylphenoxy group, 2-thfluoromethylphenoxy group, 3thfluoromethylphenoxy group, 4-trifluoxy group , 3pentafluoroethylphenoxy group, 2,3-dimethylphenoxy group, 3,4,5-trimethylphenoxy group, 4-npentylphenoxy group, 4-n-hexylphenoxy group, 2-methoxyphenoxy group, 3-methoxyphenoxy group, group

4-methoxyphenoxy, 2-ethoxyphenoxy group, 3-ethoxyphenoxy group, 4-ethoxyphenoxy group, 4n-propoxyphenoxy group, 4-ter-butoxyphenoxy group, 4-n-butoxyphenoxy group, 2thfluoromethoxyphenoxy group, 3-trifluoromethoxyphenoxy group, 3-trifluoromethoxyphenoxy group ,

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202/854 2-pentafluoroethoxyphenoxy group, 3-pentafluoroethoxyphenoxy group, 2,3dimethoxyphenoxy group, 3,4,5-trimethoxyphenoxy group, 4-n-pentyloxyphenoxy group, 4-nhexyloxyphenoxy group or the like.

[0275] A C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkoxy group) includes a C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by 1 to 3 C1-6 alkoxy group unsubstituted or substituted by halogens), for example, a benzyloxycarbonyl group, phenylethoxycarbonyl group, 3-phenylpropoxycarbonyl group, 2-phenylpropoxycarbonyl group, 4-phenylbutoxycarbonyl group, 5-phenylpentoxicarbonyl group, 4-phenylpentoxyl group, 4-phenylpentoxyl group. 6-phenylexyloxycarbonyl group, 2-methoxybenzyloxycarbonyl group, 2,4-dimethoxybenzyloxycarbonyl group, 2,4,6trimethoxybenzyloxycarbonyl group, 2-trifluoromethoxybenzyloxycarbonyl group, 3trifluoromethoxybenzyloxycarbonyl group, 4-trifluoromethoxy-methoxy-2-group 3-trifluoromethoxyphenyl) ethoxycarbonyl, group 2- (4-trifluoromethoxyphenyl) ethoxycarbonyl, group 3- (3trifluoromethoxy enyl) propoxycarbonyl, group 3- (4-trifluoromethoxyphenyl) propoxycarbonyl, group 4- (4-trifluoromethoxyphenyl) pentoxycarbonyl, group 6- (4trifluoromethoxyphenyl) hexyloxycarbonyl or similar.

[0276] A phenyl C1-6 alkylcarbamoyl group that can be substituted on the phenyl ring by at least one halogen atom includes a phenyl C1-6 alkylcarbamoyl group that can be substituted on the phenyl ring by 1 to 5 halogen atoms, for example , a benzylcarbamoyl group, 2-phenethylcarbamoyl group, 3-phenylpropylcarbamoyl group, 2-phenylpropylcarbamoyl group, 4-phenylbutylcarbamoyl group, 5-phenylpentylcarbamoyl group, 4-phenylpentylcarbamoyl group, fluorobylamyl group, fluorobylamyl group , 4.6-

trichlorobenzylcarbamoyl, group 2,3,4,5,6-pentafluorobenzylcarbamoyl, group 4- fluorobenzylcarbamoyl, group 2-chlorobenzylcarbamoyl, group 3- chlorobenzylcarbamoyl, group 4-chlorobenzylcarbamoyl, group 2- bromobenzylcarbamoyl, group 3-bromobenzylcarbamoyl, group 4- bromobenzylcarbamoyl, group 2-iodobenzylcarbamoyl, group 3-

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203/854

iodobenzylcarbamoyl, group 4-iodobenzylcarbamoyl, group 2.3- difluorobenzylcarbamoyl, group 3,4-difluorobenzylcarbamoyl, group 3.5- difluorobenzylcarbamoyl, group 2,4-difluorobenzylcarbamoyl, group 2.6- difluorobenzylcarbamoyl, group 2,3-dichlorobenzylcarbamoyl, group 3.4- dichlorobenzylcarbamoyl, group 3,5-dichlorobenzylcarbamoyl, group 2.4-

dichlorobenzylcarbamoyl, 2,6-dichlorobenzylcarbamoyl group or the like.

[0277] A phenylthio group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkoxy group) includes a phenylthio group (which can be substituted on the phenyl ring by 1 to 3 C1 alkoxy group -6 unsubstituted or substituted by halogens), for example, a phenylthio group, 2-methoxyphenylthio group, 3-methoxyphenylthio group, 4-methoxyphenylthio group, 2,4-dimethoxyphenylthio group, 2,4,6-trimethoxyphenylthio group, group 3,5 -ditrifluoromethoxyphenylthio, 2trifluoromethoxyphenylthio group, 3-trifluoromethoxyphenylthio group, 4-trifluoromethoxyphenylthio group, 4-ethoxyphenylthio group, 4-pentafluoroethoxyphenylthio group, 4-propoxyphenylthio group, 4-propylphenylthioxy group, 4butoxythiophenyl group

[0278] A phenylsulfoxide group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkoxy group) includes a phenylsulfoxide group (which can be substituted on the phenyl ring by 1 to 3 C1- alkoxy group -6 unsubstituted or substituted by halogens), for example, a phenylsulfoxide group, 2-methoxyphenylsulfoxide group, 3-methoxyphenylsulfoxide group, 4methoxyphenylsulfoxide group, 2,4-dimethoxyphenylsulfoxide group, 2,4,6trimethoxyphenylsulfoxide group, 3,5,6-ditrifluoromethoxyphenylsulfoxide group , 2trifluoromethoxyphenylsulfoxide group, 3-trifluoromethoxyphenylsulfoxide group, 4trifluoromethoxyphenylsulfoxide group or the like.

[0279] A C1-6 alkoxy pyridyl group includes, for example, 2-pyridylmethoxy group,

3-pyridylmethoxy, 4-pyridylmethoxy group, 2- (2-pyridyl) ethoxy group, 2- (3-pyridyl) ethoxy group, 2- (4-pyridyl) ethoxy group, 3- (2-pyridyl) propoxy group, group 3- (3-pyridyl) propoxy, group 3- (4-pyridyl) propoxy, group 4- (2-pyridyl) butoxy, group 4- (3-pyridyl) butoxy, group 4- (4pyridyl) butoxy, group 5- (2 -pyridyl) pentyloxy, group 5- (3-pyridyl) pentyloxy, group 5- (4-pyridyl) pentyloxy, group 6- (2-pyridyl) hexioxy, group 6- (3-pyridyl) hexyloxy, group 6- (4

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204/854 pyridyl) hexyloxy or the like.

[0280] A C2-6 phenyl alkanoyl group that can be substituted on the phenyl ring by at least one halogen atom includes a C2-6 phenyl alkanoyl group that can be substituted on the phenyl ring by 1 to 5 halogen atoms, for example , a phenylacetyl group, 3-phenylpropionyl group, 4-phenylbutyria group, 5-phenylpentanoyl group,

6-phenylexanoyl, group 2-fluorophenylacetyl, group 3-fluorophenylacetyl, group4-fluorophenylacetyl, group 2-chlorophenylacetyl, group 3-chlorophenylacetyl, group4chlorophenylacetyl, group 2-bromophenylacetyl, group 2-bromophenylacetyl, group 3-bromofen 2,4,6-trichlorophenylacetyl, group

2,3,4,5,6-pentafluorophenylacetyl, group 3- (2-fluorophenyl) propionyl, group 3- (3-fluorophenyl) propionyl, group 3- (4-fluorophenyl) propionyl, group 3- (2-chlorophenyl) propionyl, group 3- (3-chlorophenyl) propionyl, group 3- (4-chlorophenyl) propionyl, group 3- (2bromophenyl) propionyl, group 3- (3-bromophenyl) propionyl, group 3- (4bromophenyl) propionyl, group 4- ( 4-fluorophenyl) butyryl, group 4- (3-chlorophenyl) butyryl, group 4- (4-chlorophenyl) butyryl, group 5- (4-fluorophenyl) pentanoyl, group 5- (3-chlorophenyl) pentanoyl, group 5- (4- chlorophenyl) pentanoyl, group 6- (4-fluorophenyl) hexanoyl, group 5- (3-chlorophenyl) hexanoyl, group 6- (4-chlorophenyl) hexanoyl or the like.

[0281] A phenylcarbamoyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group) includes a phenylcarbamoyl group (which can be substituted on the phenyl ring by 1 to 3 C1 alkyl groups -6 unsubstituted or substituted by halogen) the amino portion of the carbamoyl group may be additionally substituted by a C1-6 alkyl group or a phenyl C1-6 alkyl group, for example, a phenylcarbamoyl group, 2methylphenylcarbamoyl group, group 3- methylphenylcarbamoyl, 4-methylphenylcarbamoyl group, 3,4-dimethylphenylcarbamoyl group, 2,4,6-trimethylphenylcarbamoyl group, 4-npropylphenylcarbamoyl group, 4-n-butylphenylcarbamoyl group, 3-n-pentylphenylcarbamoyl group, 3-n-pentylphenyl group 2-trifluoromethylphenylcarbamoyl, group 3trifluoromethylphenylcarbamoyl, group 4-tnfluoromethylphenylcarbamoyl, group N-methyl-N-phenylcarbamoyl, group N- (2-methylphenyl) -N-methylcarbamoyl, group N- (3-ethylphenyl) -NPetition 870190039560, of 04/26/2019, p. 213/876

205/854 methylcarbamoyl, N- (4-n-hexylphenyl) -N-methylcarbamoyl group, N- (2isopropylphenyl) -N-methylcarbamoyl group, N- (3-n-butylphenyl) -N-methylcarbamoyl group, group N (4 -ter-butylphenyl) -N-methylcarbamoyl, group N- (4-n-pentylphenyl) -N-methylcarbamoyl, group N-benzyl-N-phenylcarbamoyl, group N-benzyl-N- (2-trifluoromethylphenyl) carbamoyl, group N -benzyl-N- (2,3-dimethylphenyl) carbamoyl, N-benzyl-N- (2,4,6trimethylphenyl) carbamoyl group, N-benzyl-N- (3,5-ditrifluoromethylphenyl) carbamoyl group, N-benzyl group -N- (3-methylphenyl) carbamoyl, N-benzyl-N- (4-ter-butylphenyl) carbamoyl group, N-benzyl-N- (2-isopropylphenyl) carbamoyl group, N-benzyl-N- (3- npropylphenyl) carbamoyl, N-benzyl-N- (4-ethylphenyl) carbamoyl group or the like.

[0282] A piperidinyloxycarbonyl group (which can be substituted on the piperidine ring by at least one phenyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group) as a substituent) piperidinyloxycarbonyl group (which can be substituted on the piperidine ring by groups 1 to 3 phenyl (which can be substituted on the phenyl ring by 1 to 3 C1-6 alkyl groups unsubstituted or substituted by halogen) as a substituent), for example, piperidin-1-yloxycarbonyl group, piperidin-2yloxycarbonyl group, piperidin-3-yloxycarbonyl group, piperidin-4-yloxycarbonyl group, 1-phenylpiperidin-4-yloxycarbonyl group, 1,2-diphenylpiperidin-4-yloxycarbonyl group, group 1,3 , 4-triphenylpiperidin-4-yloxycarbonyl, group 1 - (2-methylphenyl) piperidin-4-yloxycarbonyl, group 1 - (3-m ethyl) piperid in-4-i loxicarbonyl, group 1 - (4-m ethyl Ifen il) piperid in-4yloxycarbonyl, group 1 - (2,4-dimethylphen nil) piperidin-4-yloxycarbonyl, group 1- (2,4,6trim eti Ifenyl) piperidin-4-yloxycarbonyl, group 1 - (2-trifluoromethylphenyl) pipendin-4yloxycarbonyl, group 1- (3-trifluoromethylphenyl) ) pipendin-4-yloxycarbonyl, group 1- (3,5ditrifluoromethylphenyl) piperidin-4-yloxycarbonyl, group 1 - (4-trifluoromethylphenyl) pipendin-4yloxycarbonyl, group 1- (2-pentafluoroethylphenyl) piperidinyl-4-yloxycarbonyl (3pentafluoroethylphenyl) piperidin-4-yloxycarbonyl, group 1 - (4-pentafluoroethylphenyl) piperidin-

4-yloxycarbonyl, group 1 - (2-n-propylphenyl) piperidin-4-yloxycarbonyl, group 1- (3-npropylphenyl) piperidin-4-yloxycarbonyl, group 1 - (4-n-propylphenyl) piperidin-4-yloxycarbonyl or similar.

[0283] A 5- to 6-membered saturated heterocycle formed by means of

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206/854 bonding R ²⁴ and R ²⁵ to each other by means of the adjacent nitrogen atom is a heterocycle by connecting R ²⁴ and R ²⁵ to each other by means of, or not through, a nitrogen atom, oxygen atom or sulfur atom together with the adjacent nitrogen atom, examples of which include a pyrrolidinyl group, piperazyl group, piperidyl group, morpholino group, thiomorpholino group or the like.

[0284] A C3-8 cycloalkyl group - C1-6 alkyl includes, for example, a cyclopropylmethyl group, 2-cyclopropiethyl group, 3-cyclopropylpropyl group, 4-cyclopropylbutyl group, 4-cyclopropylpentyl group, 6-cyclopropylexyl group, cyclobutylmethyl group, group 2-cyclobutylethyl, 3-cyclobutylpropyl group, 4-cyclobutylbutyl group, 4-cyclobutylpentyl group, 6-cyclobutylexyl group, cyclopentylmethyl group, 2-cyclopentylethyl group, 3-cyclopentylpropyl group, 4-cyclopentylbutyl group, 4cyclopentylpentyl group, 6-cyclopentylpentyl group, group 6 -hexylmethyl, 2-cyclohexylethyl group, 3-cyclohexylpropyl group, 4-cyclohexylbutyl group, 4-cyclohexylpentyl group, 6-cyclohexylexyl group, cycloheptylmethyl group, 2-cycloheptylethyl group, 3-cyclo group -heptilpropyl, group 4-cycloheptiIbutiIa, group 4-cycloheptiIpentiIa, group

6-cycloheptylhexyl, cyclooctylmethyl group, 2-cyclooctylethyl group, 3cyclooctylpropyl group, 4-cyclooctylbutyl group, 4-cyclooctylpentyl group, 6cyclooctylexyl group or the like.

[0285] A phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of a halogen atom; cyano group; C1-6 alkyl group unsubstituted or substituted by halogen ; C3-8 cycloalkyl group; C1-6 alkoxy group unsubstituted or substituted by halogen; amino group that may have a C1-6 alkyl group as a substituent; C1-6 alkoxycarbonyl group; phenoxy group; C1-6 phenyl alkyl group; C2-6 alkenyl phenyl group; pyridyl group; imidazolyl group; and piperizinyl group) includes, for example, a benzyl group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 4-phenylbutyl group , 5-phenylpentyl group, 4-phenylpentyl group, 6-phenylexyl group, 4-cyanobenzyl group, 2,3-dicyanobenzyl group, 2,4,6-tricianobenzyl group, group 2- (4cyanophenyl) ethiIa, group 3- (4 -cyanophenyl) propyl, group 2- (4-cyanophenyl) propyl, group 4- (4

Petition 870190039560, of 26/04/2019, p. 215/876

207/854 cyanophenyl) butyl, group 5- (4-cyanophenyl) pentyl, group 4- (4-cyanophenyl) pentyl, group 6 (4-cyanophenyl) hexyl, group 2-cyanobenzyl, group 2- (3-cyanophenyl) ethyl , group 3- (2-cyanophenyl) propyl, group 2- (2-cyanophenyl) propyl, group 4- (3-cyanophenyl) butyl, group 5 (2-cyanophenyl) pentyl, group 4- (3-cyanophenyl) pentyl, group 6 - (3-cyanophenyl) hexyl, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group , 2-iodobenzyl group, 3-iodobenzyl group, 4-iodobenzyl group, 2,3-difluorobenzyl group, 3,4-difluorobenzyl group, 3,5-difluorobenzyl group, 2,4-difluorobenzyl group, 2,6-difluorobenzyl group, group 2,3dichlorobenzyl, group 3,4-dichlorobenzyl, group 3,5-dichlorobenzyl, group 2,4,6trichlorobenzyl, group 2,4-dichlorobenzyl, group 2,6-dichlorobenzyl, group 2trifluorobenzyl, group 2-methylbenzyl, group 2, 4-dimethylbenzyl, group 2,4,6 trimethylben zila, 3,5-ditrifluoromethylbenzyl group, 3-trifluoromethylbenzyl group, 4trifluoromethylbenzyl group, 2-pentafluoroethylbenzyl group, 3-pentafluoroethylbenzyl group, 4-pentafluoroethylbenzyl group, 4-pentafluoroethylbenzyl group, 2-trifluoro group 3-pentafluoroethoxybenzyl group, 4-pentafluoroethoxybenzyl group, 2- (2trifluoromethylphenyl) ethyl group, 2- (3-trifluoromethylphenyl) ethyl group, 2- (4trifluoromethylphenyl) ethyl group, 2-methoxybenzyl group, 2-methoxybenzyl group, 2,4-dimethoxy group , 4,6 trimethoxybenzyl, group 3,5-ditrifluoromethoxybenzyl, group 2-chloro-4-

trifluoromethylbenzyl, 3-fluoro-4-trichloromethoxybenzyl group, group 2- (2- trifluoromethoxyphenyl) ethyl, group 2- (3-trifluoromethoxyphenyl) ethyl, group 2- (3- trifluoromethoxyphenyl) ethyl, group 2- (2-pentafluoroethoxyphenyl) ethyl, group 2- (3- pentafluoroethoxyphenyl) ethyl, group 2- (4-pentafluoroethoxyphenyl) ethyl, group 3- (2- trifluoromethylphenyl) propyl, group 3- (3-trifluoromethylphenyl) propyl, group 3- (4- trifluoromethylphenyl) propyl, group 3- (2-trifluoromethoxyphenyl) propyl, group 3- (3- trifluoromethoxyphenyl) propyl, group 3- (4-trifluoromethoxyphenyl) propyl, group 3- (3- pentafluoroethoxyphenyl) propyl, group 3- (4-pentafluoroethoxyphenyl) propyl, group 4- (3- pentafluoroethoxyphenyl) butyl, group 5- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethoxyphenyl) pentyl, group 6- (3-

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208/854 trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethylphenyl) hexyl, group 6- (4trifluoromethoxyphenyl) hexyl, group 2-cyclohexylbenzyl, group 3-cyclohexylbenzyl, group 4-cyclohexylbenzyl, group 2- ( 2-cyclohexylphenyl) ethyl, group 2- (3-cyclohexylphenyl) ethyl, group 2- (4-cyclohexylphenyl) ethyl, group 3- (2-cyclohexylphenyl) propyl, group 3- (3- cyclohexylphenyl) propyl, group 3- (4-cyclohexylphenyl) propyl, group 3-aminobenzyl, group 2,4diaminobenzyl, group 2,4,6-triaminobenzyl, group 2-dimethylaminobenzyl, group 3dimethylaminobenzyl, group 4-dimethylaminobenzyl, group 2 - (2-dimethylaminophenyl) ethyl, group 2- (3-dimethylaminophenyl) ethyl, group 2- (4-dimethylaminophenyl) ethyl, dimethylaminophenyl) propyl, dimethylaminophenyl) propyl, methoxycarbonylbenzyl, methoxycarbonylphenyl) ethyl, methoxycarbonyl), methoxycarbonyl group group group group group group

3- (3-dimethylaminophenyl) propyl,

2-methoxycarbonylbenzyl,

4-methoxycarbonylbenzyl,

2- (3-methoxycarbonylphenyl) ethyl,

3- (2-methoxycarbonylphenyl) propyl,

3- (4-methoxycarbonylphenyl) propyl, group group group group group group group

3- (23- (432- (2-

2- (4-

3- (3-

2ethoxycarbonylbenzyl, 3-ethoxycarbonylbenzyl group, 4-ethoxycarbonylbenzyl group, 2- (2-ethoxycarbonylphenyl) ethyl group, 2- (3-ethoxycarbonylphenyl) ethyl group, 2- (4ethoxycarbonylphenyl) ethyl group, 3- (2-ethoxycarbonylphenyl) group group 3- (3ethoxycarbonylphenyl) propyl, group 3- (4-ethoxycarbonylphenyl) propyl, group 2-phenoxybenzyl, group 3-phenoxybenzyl, group 4-phenoxybenzyl, group 2-stirylbenzyl, group 3styrylbenzyl, group 4-stirylbenzyl, group 2- ( 2-phenoxyphenyl) ethyl, group 2- (3-phenoxyphenyl) ethyl, group 2- (4-phenoxyphenyl) ethyl, group 3- (2-phenoxyphenyl) propyl, group 3- (3-phenoxyphenyl) propyl, group 3- (4-phenoxyphenyl) propyl, group 2-benzylbenzyl, group 3 benzylbenzyl, group 4-benzylbenzyl, group 2- (2-benzylphenyl) ethyl, group 2- (3-benzylphenyl) ethyl, group 2- (4-benzylphenyl) ethyl, group 3- (2- benzylphenyl) propyl, group 3- (3benzylphenyl) propyl, group 3- (4-benzylphenyl) propyl, group 2- (2-phenethyl) benzyl, group 3 (2-phenethyl) benzyl, group 4- (2-phenethyl) benzyl , 2- (2- (1-phenethyl) phenyl) ethyl group, group 2 (3- (2-phenethyl) phenyl) ethyl, group 2- (4- (2-phenethyl) phenyl) ethyl, group 2- (3- (2-phenethyl) phenyl) propyl, group 3- (2- (2 -phenethyl) phenyl) propyl, group 3- (4- (1-phenethyl) phenyl) propyl, group 2- (3-pyridyl) benzyl, group 3- (3-pyridyl) benzyl, group 4- (3pyridyl) benzyl, group 2 - (1-imidazolyl) benzyl, group 3- (1-imidazolyl) benzyl, group 4- (1

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209/854 imidazolyl) benzyl, group 2- (1-piperidino) benzyl, group 3- (1-piperidino) benzyl, group 4- (1-piperidino) benzyl or the like.

[0286] A biphenylyl C1-6 alkyl group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a group C1-6 alkoxy unsubstituted or substituted by halogen and an amino group that may have a C1-6 alkyl group as a substituent) includes a biphenylyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5, from preferably 1 to 3 groups selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen and an amino group that may have from 1 to 2 C1-6 alkyl groups as a substituent), for example, 2-biphenylylmethyl, 3-biphenylylmethyl group, 4-biphenylylmethyl group, 2- (2-biphenylyl) ethyl group, 2- (3biphenylyl) ethyl group, group 2- (4-biphenyl) ethyl, group 3- (2-biphen ylyl) propyl, group 3- (3biphenylyl) propyl, group 3- (4-biphenylyl) propyl, group 4- (4-biphenylyl) butyl, group 5- (4biphenylyl) pentyl, group 6- (4-biphenylyl) hexyl, 2'-fluoro-2-biphenylmethyl group, 2'fluoro-3-biphenylmethyl group, 2'-fluoro-4-biphenylmethyl group, 3'-fluoro-2-biphenylmethyl group, 3'-fluoro-3-biphenylmethyl group, group 3'-fluoro-4-biphenylmethyl, group 4'-fluoro-2biphenylImethyl, group 4'-fluoro-3-biphenylImethyl, group 4'-fluoro-4-biphenylImethyl, group 2'chloro-2-biphenylmethyl, group 2'- chloro-3-biphenylylmethyl, group 2'-chloro-4-biphenylylmethyl, group 3'-chloro-2-biphenylylmethyl, group 3'-chloro-3-biphenylylmethyl, group 3'-chloro-4biphenylylmethyl, group 4'-chloro- 2-biphenylylmethyl, group 4'-chloro-3-biphenylylmethyl, group 4'chloro-4-biphenylmethyl, group 2 ', 4'-dichloro-4-biphenylylmethyl, group 2', 4 ', 6'-trichloro-3biphenylylmethyl, group 3 ', 5'-ditritrifluoromethyl-4-biphenylethyl, group 2', 3 ', 4', 5 ', 6'pentafluoro-3-biphenylylmethyl, group 2'-methyl-2-biphenylylmethyl, group 2 '-methyl-3biphenylylmethyl, group 2'-methyl-4-biphenylylmethyl, group 3'-methyl-2-biphenylylmethyl, group 3'methyl-3-biphenylylmethyl, group 3'-methyl-4-biphenylylmethyl, group 4'-methyl -2-biphenylylmethyl, 4'-methyl-3-biphenylylmethyl group, 4'-methyl-4-biphenylmethyl group, 2'-trifluoromethyl-2biphenylmethyl group, 2'-trifluoromethyl-3-biphenylmethyl group, 2'-trifluoromethyl-methyl group , 3'-trifluoromethyl-2-biphenylylmethyl group, 3'-trifluoromethyl-3 groupPetition 870190039560, of 26/04/2019, p. 218/876

210/854 biphenylylmethyl, 3'-trifluoromethyl-4-biphenylylmethyl group, 4'-trifluoromethyl-2biphenylylmethyl group, 4'-trifluoromethyl-3-biphenylylmethyl group, 4'-trifluoromethyl-4biphenylmethyl-methyl-2'-group 2' , 2'-methoxy-3-biphenyl methyl group, 2'-methoxy-4-biphenyl methyl group, 3'-methoxy-2-biphenyl methyl group, 3'-methoxy-3 biphenyl methyl group, 2 ', 4'-dimethoxy-3- group biphenylylmethyl, group 2 ', 4', 6'-trimethoxy-4biphenylylmethyl, group 2'-methoxy-4'-trifluoromethyl-2-biphenylylmethyl, group 3'-methyl-4'trifluoromethoxy-2-biphenylylmethyl, group 2'-chloro -4'-trifluoromethoxy-3-biphenylylmethyl, group 3'-methoxy-4-biphenylmethyl, group 4'-methoxy-2-biphenylylmethyl, group 4'-methoxy-3biphenylImethyl, group 4'-methoxy-4-biphenylImetiIa, group 2 '-trifluoromethoxy-2-biphenylmethyl, group 2'-trifluoromethoxy-3-biphenylmethyl, group 2'-trifluoromethoxy-4-biphenylylmethyl, group 3'-trifluoromethoxy-2-biphenylylmethyl, group 3'-trifluoromethoxy, 3-trifluoromethoxy 'trif fluoromethoxy-4-biphenylmethyl, group 4'-trifluoromethoxy-2-biphenylylmethyl, group 4'trifluoromethoxy-3-biphenylmethyl, group 4'-trifluoromethoxy-4-biphenylmethyl, group 2- (4'trifluoromethyl-4-group), group 2- 3- (4'-trifluoromethoxy-4-biphenylyl) propyl, group 3- (4'trifluoromethoxy-4-biphenylyl) propyl, group 4- (4'-trifluoromethoxy-4-biphenylyl) butyl, group 5 (4'-trifluoromethoxy -4-biphenylyl) pentyl, group 6- (4'-trifluoromethoxy-4-biphenylyl) hexyl, 4'-dimethylamino-3-biphenylylmethyl group, 4'-dimethylamino-4-biphenylyl methyl group or the like. [0287] A C1-6 alkyl naphthyl group includes, for example, group 1-naphthylmethyl, group

2-naphthylmethyl, group 2- (1-naphthyl) ethyl, group 1- (2-naphthyl) ethyl, group 3- (1-naphthyl) propyl, group 3- (2-naphthyl) propyl, group 4- (1 - naphthyl) butyl, group 4- (2-naphthyl) butyl, group 5- (1-naphthyl) pentyl, group 5- (2-naphthyl) pentyl, group 6- (1-naphthyl) hexyl, group 6- (2-naphthyl) hexyl or similar.

[0288] A phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom; cyano group; amino group which may have a C1-6 alkyl group as a substituent; group C1-6 alkyl unsubstituted or substituted by halogen; C1-6 alkoxy group unsubstituted or substituted by halogen; C1-6 alkoxycarbonyl group; carboxyl group; phenoxy group (which can be substituted on the phenyl ring by at least one group selected from one group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group and unsubstituted C1-6 alkoxy group or

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211/854 replaced by halogen); C1-6 alkyl amino group (which may have at least one group selected from the group consisting of a phenyl group in the amino group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of an atom of halogen, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) and a C1-6 alkyl group); and a phenyl C1-6 alkoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) includes a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom; cyano group; amino group that may have a C1-6 alkyl group as a substituent; C1-6 alkyl group unsubstituted or substituted by halogen; C1-6 alkoxy group unsubstituted or substituted by halogen; C1-6 alkoxycarbonyl group; carboxyl group; phenoxy group (which may be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, unsubstituted C1-6 alkyl group or substituted by halogen and alkoxy group Ci-6 not substituted or substituted by halogen); amino C1-6 alkyl group (which can have 1 to 2 groups in the amino group selected from a group consisting of a phenyl group (which can be replaced on the phenyl ring by 1 to 5, preferably 1 to 3 selected groups) a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) and a C1-6 alkyl group); and a phenyl C1-6 alkoxy group (which can be substituted on the phenyl ring by 1 to 5, preferably from 1 to 3 groups selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group halogen and C1-6 alkoxy group not substituted or substituted by halogen), for example, a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, group 4 -chlorophenyl, group 2-bromophenyl, group 3-bromophenyl, group 4-bromophenyl, group 2-iodophenyl, group 3-iodophenyl, group 4-iodophenyl, group

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212/854

2,3-difluorophenyl, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2,4difluorophenyl group, 2,6-difluorophenyl group, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, group 3,5 -dichlorophenyl, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4,5trifluorophenyl group, 2,3,4,5,6-pentafluorophenyl group, 3,4,5-trichlorophenyl group, group 2,4 , 6trifluorophenyl, 2,4,6-trichlorophenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2,4-dicianophenyl group, 2,4,6-tricianophenyl group, 2methylphenyl group, 3-methylphenyl group , 4-methylphenyl group, 2,3-dimethylphenyl group, group

2,4,6-trimethylphenyl, 2-methyl-3-chlorophenyl group, 3-methyl-4-chlorophenyl group, 2chloro-4-methylphenyl group, 2-methyl-3-fluorophenyl group, 2-trifluoromethylphenyl group, 3trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-pentafluoroethylphenyl group, 3pentafluoroethylphenyl group, 4-pentafluoroethylphenyl group, 2-isopropylphenyl group, 3isopropylphenyl group, 4-isopropylphenyl group, 2-ter-butylphenyl group, 3-tert-butylphenyl group butylphenyl, group 2-sec-butylphenyl, group 3-sec-butylphenyl, group 4-secbutilphenyl, group 2-n-heptafluoropropylphenyl, group 3-n-heptafluoropropylphenyl, group 4-n-heptafluoropropylphenyl, group 4-pentylphenyl hexylphenyl, 2methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2,4-dimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, 2-methoxy-3-chlorophenyl group, 2-fluoro-3methoxyphenyl group, group 2- fluoro-4-methoxyphenyl, group 2,6-dimethoxyphenyl, group 2,3,4trifluorophenyl, group 2-trifluoromethoxyphenyl, group 3-trifl uoromethoxyphenyl, group 4trifluoromethoxyphenyl, group 2-pentafluoroethoxyphenyl, group 3-pentafluoroethoxyphenyl, group 4-pentafluoroethoxyphenyl, group 2-isopropoxyphenyl, group 3-isopropoxyphenyl, group 4-isopropoxyphenyl, group 2-ter-group 4-terbutoxyphenyl, group 2-sec-butoxyphenyl, group 3-sec-butoxyphenyl, group 4-secbutoxyphenyl, group 2-n-heptafluoropropoxyphenyl, group 3-n-heptafluoropropoxyphenyl, group 4-n-heptafluoropropoxyphenyl, group 4-group 4-hexyloxyphenyl, 3-aminophenyl group, 4-methylaminophenyl group, 2-dimethylaminophenyl group, 3dimethylaminophenyl group, 4-dimethylaminophenyl group, 2-methoxycarbonylphenyl group, 3methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group, 3-group 2-group -carboxyphenyl, 2,3-dicarboxyphenyl group, 2,4,6tricarboxyphenyl group, 2-ethoxycarbonylphenyl group, 3-ethoxycarbonylphenyl group, group 4

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213/854 ethoxycarbonylphenyl, 2,3-diethoxycarbonylphenyl group, 2,4,6-trimethoxycarbonylphenyl group, 2-phenoxyphenyl group, 3-phenoxyphenyl group, 4-phenoxyphenyl group, group 2- (2-chlorophenoxy) phenyl, group 2- (3- chlorophenoxy) phenyl, group 2- (4-chlorophenoxy) phenyl, group 3 (2-chlorophenoxy) phenyl, group 3- (3-chlorophenoxy) phenyl, group 3- (4-chlorophenoxy) phenyl, group 4- (2-chlorophenoxy ) phenyl, group 4- (3-chlorophenoxy) phenyl, group 4- (4-chlorophenoxy) phenyl, group 2- (2-trifluoromethylphenoxy) phenyl, group 2- (3-trifluoromethylphenoxy) phenyl, group 2- (3methylphenoxy) phenyl , group 2- (2,3-dimethylphenoxy) phenyl, group 2- (3,4,5-trimethylphenoxy) phenyl, group 2- (4-trifluoromethylphenoxy) phenyl, group 3- (2-trifluoromethylphenoxy) phenyl, group 3- (3-

trifluoromethylphenoxy) phenyl, group 3- (4-trifluoromethylphenoxy) phenyl, group 4- (2- trifluoromethylphenoxy) phenyl, group 4- (3-trifluoromethylphenoxy) phenyl, group 4- (4- trifluoromethylphenoxy) phenyl, group 2- (3-methoxyphenoxy) phenyl, group 2- (2,3- dimethoxyphenoxy) phenyl, group 2- (3,4,5-trimethoxyphenoxy) phenyl, group 2- (2- trifluoromethoxyphenoxy) phenyl, group 2- (3-trifluoromethoxyphenoxy) phenyl, group 2- (4- trifluoromethoxyphenoxy) phenyl, group 3- (2-trifluoromethoxyphenoxy) phenyl, group 3- (3- trifluoromethoxyphenoxy) phenyl, group 3- (4-trifluoromethoxyphenoxy) phenyl, group 4- (2- trifluoromethoxyphenoxy) phenyl, group 4- (3-trifluoromethoxyphenoxy) phenyl, group 4- (4-

trifluoromethoxyphenoxy) phenyl, 4-aminomethylphenyl group, 4-methylaminomethylphenyl group, 4-dimethylaminomethylphenyl group, 4-diethylaminomethylphenyl group, 4-di (npropyl) aminomethylphenyl group, group 4- (phenylaminomethyl) phenyl, group 4- (2phenyl) 4- (3-phenylaminopropyl) phenyl, group 4- (N-methyl-N-phenylaminomethyl) phenyl, group 4- (2-N-methyl-N-phenylaminoethyl) phenyl, group 4- (3-N-ethyl-N-phenylaminopropyl) phenyl , group 4- (4-chlorophenylaminomethyl) phenyl, group 4- [2- (4-chlorophenylamino) ethyl] phenyl, group 4- [3- (4-chlorophenylamino) propyl] phenyl, group 4- [N-methylN-4-chlorophenylamino ] methyl] phenyl, group 4- [2- (N-methyl-N-4-chlorophenylamino) ethyl] phenyl, group 4- [3- (N-ethyl-N-4-chlorophenylamino) propyl] phenyl, group 4- (4trifluoromethylphenylaminomethyl) phenyl, group 4- [2- (4-trifluoromethylphenylamino) ethyl] phenyl, group 4- [2- (4-methylphenylamino) methyl] phenyl, group 4- [2- (2,4-dimethylphenylamino) methyl] phenyl, group 4- [2- (2,4,6-trimethylphenylamino) methyl] phenyl, group 4 [3- (3,5-ditrifluoromethylphenylamino) propyl] phen ila, group 4- [N-methyl-N-4trifluoromethylphenylamino] methyl] phenyl, group 4- [2- (N-methyl-N-4

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214/854 trifluoromethylphenylamino) ethyl] phenyl, 4- [3- (N-ethyl-N-4-trifluoromethylphenylamino) propyl] phenyl, group 4- [2- (3-methoxyphenylamino) methyl] phenyl, group 4- [2- (2,4 dimethoxyphenylamino) methyl] phenyl, group 4- [2- (2,4,6-trimethoxyphenylamino) methyl] phenyl, group 4- (4-trifluoromethoxyphenylaminomethyl) phenyl, group 4- [2- (3,5 ditrifluoromethoxyphenylamino ) ethyl] phenyl, trifluoromethoxyphenylamino) propyl] phenyl, trifluoromethoxyphenylamino] methyl] phenyl, trifluoromethoxyphenylamino) ethyl] phenyl, group 4- [3- (4 group 4- [N-methyl-N-4 group 4- [2- (N -methyl-N-4 group 4- [3- (N-ethyl-N-4 trifluoromethoxyphenylamino) propyl] phenyl, group 4-benzyloxyphenyl, group 4- (4chlorobenzyloxy) phenyl, group 4- [2- (2,3- dichlorophenyl) ethoxy] phenyl, group 4- [3- (4chlorophenyl) propoxy] phenyl, group 4- [4- (2,4,6-trichlorophenyl) butoxy] phenyl, group 4- (4methylbenzyloxy) phenyl, group 4- ( 3,4-dimethylbenzyloxy) phenyl, group 4- (2,4,6trimethylbenzyloxy) phenyl, group 4- (4-trifluoromethylbenzyloxy) phenyl, group 4- [2- (4trifluoromethylphenyl) ethoxy] phenyl, group po 4- [3- (4-trifluoromethylphenyl) propoxy] phenyl, group 4 [4- (4-trifluoromethylphenyl) butoxy] phenyl, group 4- (4-trifluoromethoxybenzyloxy) phenyl, group 4 (4-methoxybenzyloxy) phenyl, group 4 - (3,4-dimethoxybenzyloxy) phenyl, group 4- (2,4,6-trimethoxybenzyloxy) phenyl, group 4- [2- (4-trifluoromethoxyphenyl) ethoxy] phenyl, group 4- [3- (4trifluoromethoxyphenyl) propoxy] phenyl, group 4- [4- (4-trifluoromethoxyphenyl) butoxy] phenyl or the like.

[0289] A biphenylyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group) includes a biphenylyl group (which can be substituted on the phenyl ring by 1 to 3 C1 alkyl groups -6 unsubstituted or substituted by halogen), for example, a 2-biphenylyl group, group

3-biphenylyl, group 4-biphenylyl, group 2'-methyl-2-biphenylyl, group 2'-methyl-3-biphenylyl, group 2'-methyl-4-biphenylyl, group 3'-methyl-2-biphenylyl, group 3'-methyl-3-biphenylyl, 3'methyl-4-biphenylyl group, 4'-methyl-2-biphenylyl group, 4'-methyl-3-biphenylyl group, 4'-methyl-4biphenylyl group, group 3 ', 4'-dimethyl-2-biphenylyl, group 2 ', 4', 6'-trimethyl-3-biphenylyl, group 2'trifluoromethyl-4 ', 6'-dimethyl-3-biphenylyl, group 2'-trifluoromethyl-2- biphenylyl, 2'trifluoromethyl-3-biphenylyl group, 2'-trifluoromethyl-4-biphenylyl group, 3'-trifluoromethyl-2biphenylyl group, 3'-trifluoromethyl-3-biphenylyl group, 3'-trifluoromethyl-4-biphenyl group 4 '

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215/854 trifluoromethyl-2-biphenylyl, 4'-trifluoroethyl-3-biphenylyl group, 4'-trifluoromethyl-4biphenylyl group or the like.

[0290] An amino group substituted by a C1-6 alkoxycarbonyl group includes an amino group which is substituted by a C1-6 alkoxycarbonyl group and may have a C1-6 alkyl group as another substituent on the amino group, for example, a methoxycarbonylamino group , ethoxycarbonylamino group, n-propoxycarbonylamino group, isopropoxycarbonylamino group, ter-butoxycarbonylamino group, npentoxicarbonylamino group, n-hexyloxycarbonylamino group, N-methyl-Nmethoxycarbonylamino group, N-ethoxycarbonyl-N-methyl-methylamino group ) amino, N-methyl-N- (isopropoxycarbonyl) amino group, N- (terbutoxycarbonyl) -N-methylamino group, N-methyl-N- (n-pentoxycarbonyl) group amino, N- (nhexyloxycarbonyl) -N-methylamino group , N-ethyl-N-methoxycarbonylamino group, N-ethyl-Netoxicarbonylamino group, N-ethyl-N- (n-propoxycarbonyl) amino group, N-ethyl-Nisopropoxycarbonylamino group, N- (ter-butoxycarbonyl) -N-ethylamino group , N-ethyl-N- (npentoxicarbonyl) amino group, N-ethyl-N- (n-hexyloxycarbonyl) amino group or similar.

[0291] A phenylamino group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom and an unsubstituted or substituted halogen C1-6 alkyl group) includes an amino group having 1 to 2 phenyl groups (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom and a C1-6 alkyl group unsubstituted or substituted by halogen ), for example, a phenylamino group, 2-methylphenylamino group, 3methylphenylamino group, 4-methylphenylamino group, 2-ethylphenylamino group, 3-ethylphenylamino group, 4-ethylphenylamino group, 4-propylphenylamino group, 4-terylbutylphenylamino group , 2-trifluoromethylphenylamino group, 3-trifluoromethylphenylamino group, group

4-trifluoromethylphenylamino, 2-pentafluoroethylphenylamino group, 3pentafluoroethylphenylamino group, 2,3-dimethylphenylamino group, 3,4,5-trimethylphenylamino group, 4-pentylphenylamino group, 4-hexylphenylamino group, N-phenylamino group amino group, 2-fluorophenylamino group, 3-fluorophenylamino group, 4-fluorophenylamino group, 2-chlorophenylamino group, 3-chlorophenylamino group, 4-chlorophenylamino group, group 2

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216/854 bromophenylamino, group 3-bromophenylamino, group 4-bromophenylamino, group 2iodophenylamino, group 3-iodophenylamino, group 4-iodophenylamino, group 2,3difluorophenylamino, group 3,4-difluorophenylamino, group 3,5-difluorin, group 3,5-difluoram 4-difluorophenylamino, 2,6-difluorophenylamino group, 2,3-dichlorophenylamino group, 3,4-dichlorophenylamino group, 3,5-dichlorophenylamino group, 2,4-dichlorophenylamino group, 2,6-dichlorophenylamino group, group 3,4 , 5-trifluorophenylamino, group 2,3,4,5,6pentafluorophenylamino, group 3,4,5-trichlorophenylamino, group 2,4,6-trifluorophenylamino, group 2,4,6-trichlorophenylamino or similar.

[0292] A benzoyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one halogen atom as a substituent) includes a benzoyl C1-6 alkyl group (which can have 1 to 5 halogen atoms as a substituent on the phenyl ring), for example, a benzoylmethyl group, 2-fluorobenzoylmethyl group, 3-fluorobenzoylmethyl group, 4-fluorobenzoylmethyl group, 2-chlorobenzoylmethyl group, methyl (2,3-dichlorobenzoyl) group, group (2,4,6 -trichlorobenzoyl) methyl, group (2,3,4,5,6pentafluorobenzoyl) methyl, 3-chlorobenzoylmethyl group, 4-chlorobenzoylmethyl group, 2-bromobenzoylmethyl group, 3-bromobenzoylmethyl group, 4bromobenzoylmethyl group, 2-benzoylethyl group, group 2- (2-fluorobenzoyl) ethyl, group 2- (3-fluorobenzoyl) ethyl, group 2- (4-fluorobenzoyl) ethyl, group 2- (2-chlorobenzoyl) ethyl, group

2- (3-chlorobenzoyl) ethyl, group 2- (4-chlorobenzoyl) ethyl, group 3- (2-chlorobenzoyl) propyl, group 3- (3-chlorobenzoyl) propyl, group 3- (4-chlorobenzoyl) propyl, group 4- (2-chlorobenzoyl) butyl, group 4- (3-chlorobenzoyl) butyl, group 4- (4-chlorobenzoyl) butyl, group 5- (2-chlorobenzoyl) pentyl, group 5- (3-chlorobenzoyl) pentyl, group 5- (4-chlorobenzoyl) pentyl, group 6- (2-chlorobenzoyl) hexyl, group 6- (3-chlorobenzoyl) hexyl, group 6- (4-chlorobenzoyl) hexyl or the like.

[0293] A phenylcarbamoyl C1-6 alkyl group (which can be substituted on the phenyl ring by at least one of the unsubstituted or halogen substituted C1-6 alkyl groups) includes a phenylcarbamoyl C1-6 alkyl group (which can be substituted on the ring phenyl by 1 to 3 groups of C1-6 alkyl groups unsubstituted or substituted by halogen), for example, a phenylcarbamoylmethyl group, 2methylphenylcarbamoylmethyl group, 3-methylphenylcarbamoylmethyl group, group 4 Petition 870190039560, of 26/04/2019, p. 225/876

217/854 group group group

2,3-dimethylphenylcarbamoylmethyl,

2,6-dimethylphenylcarbamoylmethyl,

2-trifluoromethylphenylcarbamoylmethyl, group 2,4group 2,4,6group 3group 4- (n-propylphenyl) carbamoylmethyl, group 22- (3-trifluoromethylphenylcarbamoylmethyl, trimethylcarbamylmethylmethyl, methylcarbonylmethyl) 2,3ditrifluorometilfenilcarbamoilmetila group, 2,4-ditrifluorometilfenilcarbamoilmetila group, 2,6-ditrifluorometilfenilcarbamoilmetila group, 2pentafluoroetilfenilcarbamoilmetila group, 3-pentafluoroetilfenilcarbamoilmetila, 4-pentafluoroetilfenilcarbamoilmetila group, 2- (n-propylphenyl) carbamoilmetila, group 3 (n-propylphenyl) carbamoilmetila , (phenylcarbamoyl) ethyl, trifluoromethylphenylcarbamoyl group) ethyl, group 2- (2,3-ditrifluoromethylphenylcarbamoyl) ethyl, group

2- (2,4-ditrifluoromethylphenylcarbamoyl) ethyl, group 2- (2,6-ditrifluoromethylphenylcarbamoyl) ethyl, group 2- (2-pentafluoroethylphenylcarbamoyl) ethyl, group

2- (3-pentafluoroethylphenylcarbamoyl) ethyl, group 2- (4-pentafluoroethylphenylcarbamoyl) ethyl, group 3- (phenylcarbamoyl) propyl, group 3- (3-trifluoromethylphenylcarbamoyl) propyl, group

3- (4-trifluoromethylphenylcarbamoyl) propyl, group 3- (2,3-ditrifluoromethylphenylcarbamoyl) propyl, group 3- (2,4ditrifluoromethylphenylcarbamoyl) propyl, group 3- (2,6group group ditrifluoromethylphenylcarbamoyl) propyl, group 3- (2- pentafluoroethylphenylcarbamoyl) propyl, group 3- (3-pentafluoroethylphenylcarbamoyl) propyl, group 3- (4pentafluoroethylphenylcarbamoyl) propyl, group 4- (4-trifluoromethylphenylcarbamoyl) butyl, group 5- (4-trifluoromethylfamilyl) or similar.

[0294] A thiazolyl C1-6 alkyl group (which may be substituted on the thiazole ring by at least one group selected from a group consisting of an unsubstituted or halogen-substituted phenyl group and a C1-alkyl group) includes a group thiazolyl C1-6 alkyl (which can be substituted on the thiazole ring by 1 to 2 groups selected from a group consisting of an unsubstituted or substituted phenyl group with halogen and a C1-6 alkyl group), for example, group 4- thiazolylmethyl, group 5 thiazolylmethyl, group 2-methyl-4-thiazolylmethyl, group 2-methyl-5-thiazolylmethyl, group 2.5

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218/854 dimethyl-4-thiazolylmethyl, 2,4-dimethyl-5-thiazolylmethyl group, 2-methyl-5-phenyl-4thiazolylmethyl group, 2-methyl-4-phenyl-5-thiazolylmethyl group, 2-phenyl-4 group -thiazolylmethyl, 2-phenyl-5-thiazolylmethyl group, 2-phenyl-5-methyl-4-thiazolylmethyl group, 2-phenyl-4-methyl-5 thiazolylmethyl group, 2-methyl-5- (2-fluorophenyl) -4 group -thiazolylmethyl, 2-methyl-4- (2fluorophenyl) -5-thiazolylmethyl, group 2- (2-chlorophenyl) -4-thiazolylmethyl, group 2- (2bromophenyl) -5-thiazolylmethyl, group 2- (2-fluorophenyl) -5-methyl-4-thiazolylmethyl, group 2- (2-fluorophenyl) -4-methyl-5-thiazolylmethyl, group 2-methyl-5- (3-iodophenyl) -4-thiazolylmethyl, group 2-methyl-4- (3 -fluorophenyl) -5-thiazolylmethyl, group 2- (2,3-difluorophenyl) -4-thiazolylmethyl, group 2- (3-fluorophenyl) -5-thiazolylmethyl, group 2- (3-fluorophenyl) -5-methyl-4 -thiazolylmethyl, group 2- (3-fluorophenyl) -4-methyl-5-thiazolylmethyl, group 2-methyl-5- (2,4,6-trichlorophenyl) -4thiazolylmethyl, group 2-methyl-4- (2,3 , 4,5,6-pentafluorophenyl) -5-thiazolylmethyl, group 2- (4fluorophenyl) -4- thiazolylmethyl, group 4- (2-fluorophenyl) -5-thiazolylmethyl, group 2- (4-fluorophenyl) -5-methyl-4-thiazoliImetiIa, group 2- (4-fluorophenyl) -4-methyl-5-thiazolylmethyl, group 2- methyl-5- (2-chlorophenyl) -4-thiazolylmethyl, 2-methyl-4- (2-chlorophenyl) -5-thiazolylmethyl group, group 2- (2-chlorophenyl) -4-thiazolylmethyl, group 2- (2- chlorophenyl) -5-thiazolylmethyl, group 2- (2chlorophenyl) -5-methyl-4-thiazolylmethyl, group 2- (2-chlorophenyl) -4-methyl-5-thiazolylmethyl, group 2-methyl-5- (3-chlorophenyl ) -4-thiazolylmethyl, 2-methyl-4- (3-chlorophenyl) -5-thiazolylmethyl group, 2- (3-chlorophenyl) -4-thiazolylmethyl, group 2- (2-fluorophenyl) -5-thiazolylmethyl, group 2 (3-chlorophenyl) -5-methyl-4-thiazolylmethyl, group 2- (3-chlorophenyl) -4-methyl-5-thiazolylmethyl, group 2-methyl-5- (4-chlorophenyl) -4-thiazolylmethyl, group 2-methyl-4- (4-chlorophenyl) -5thiazolylmethyl, group 2- (4-chlorophenyl) -4-thiazolylmethyl, group 2- (4-chlorophenyl) -5thiazolylmethyl, group 2- (4-chlorophenyl) -5-methyl -4-thiazolylmethyl, group 2- (4-chlorophenyl) -4methyl-5-thiazolylmethyl, group 2- (2-ti azolyl) ethyl, group 2- (4-thiazolyl) ethyl, group 2- (5-thiazolyl) ethyl, group 2- (2-methyl-4-thiazolyl) ethyl, group 2- (2-methyl-5-thiazolyl) ethyl, group 2 (2,5-dimethyl-4-thiazolyl) ethyl, group 2- (2,4-dimethyl-5-thiazolyl) ethyl, group 2- (2-methyl-5-phenyl-

4-thiazolyl) ethyl, group 2- (2-methyl-4-phenyl-5-thiazolyl) ethyl, group 2- (2-phenyl-4-thiazolyl) ethyl, group 2- (2-phenyl-5-thiazolyl) ethyl, group 2- (2-phenyl-5-methyl-4-thiazolyl) ethyl, group 3- (2-thiazolyl) propyl, group 2- (4-thiazolyl) propyl, group 3- (5-thiazolyl) propyl, group 3 - (2-methyl4-thiazolyl) propyl, group 2- (2-methyl-5-thiazolyl) propyl, group 3- (2,5-dimethyl-4 thiazolyl) propyl, group 3- (2,4-dimethyl-5- thiazolyl) propyl, group 3- (2-methyl-5-phenyl-4-

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219/854 group group group

3- (2-methyl-4-phenyl-5-thiazolyl) propyl,

3- (3-phenyl-5-thiazolyl) propyl, group

4- (2-thiazolyl) butyl, group 4- (4-thiazolyl) butyl, group 3- (5group 2- (2-phenyl-43- (2-phenyl-5-methyl-4thiazolyl) propyl, thiazolyl) propyl, thiazolyl) propyl, thiazolyl) butyl, group 4- (2-methyl-4-thiazolyl) butyl, group 4- (2-methyl-5-thiazolyl) butyl, group

4- (2,5-dimethyl-4-thiazolyl) butyl, group 4- (2,4-dimethyl-5-thiazolyl) butyl, group 4- (2-methyl-5-phenyl-4-thiazolyl) butyl, group 4- (2-methyl-4-phenyl-5-thiazolyl) butyl, group 4- (2-phenyl-4-thiazolyl) butyl, group 4-phenyl-5-thiazolyl) butyl, group 4- (2-phenyl-5-methyl- 4-thiazolyl) butyl, group 5- (2-thiazolyl) pentyl, group 5- (4-thiazolyl) pentyl, group 5- (5-thiazolyl) pentyl, group

5- (2-methyl-4-thiazolyl) pentyl, group 5- (2-methyl-5-thiazolyl) pentyl, group 5- (2,5-dimethyl-4thiazolyl) pentyl, thiazolyl) pentyl, thiazolyl) pentyl, thiazolyl ) pentyl, thiazolyl) hexyl, group 5- (2-methyl-4-thiazolyl) hexyl, group 5- (2-methyl-5-thiazolyl) hexyl, group group group group group

5- (2,4-dimethyl-5-thiazolyl) pentyl, group

5- (2-methyl-4-phenyl-5-thiazolyl) pentyl,

5- (4-phenyl-5-thiazolyl) pentyl, group

5- (2-thiazolyl) hexyl, group 5- (4-thiazolyl) hexyl, group 5- (55- (2-methyl-5-phenyl-4- group 5- (2-phenyl-45- (2-phenyl-5 -methyl-4-

5- (2,5-dimethyl-4-thiazolyl) hexyl, group 5- (2,4-dimethyl-5-thiazolyl) hexyl, group 5- (2-methyl-5-phenyl-4-thiazolyl) hexyl, group 5- (2-methyl-4-phenyl-5-thiazolyl) hexyl, group 5- (2-phenyl-4-thiazolyl) hexyl, group 5- (4-phenyl-5-thiazolyl) hexyl, group 5- (2-phenyl-5 -methyl-4-thiazolyl) hexyl or the like.

[0295] An oxazolyl C1-6 alkyl group (which can be substituted on the oxazole ring by at least one group selected from a group consisting of an unsubstituted or halogen-substituted phenyl group and a C1-8 alkyl group) includes a group oxazolyl C1-6 alkyl (which can be substituted on the oxazole ring by 1 to 2 groups selected from a group consisting of an unsubstituted phenyl group or substituted by halogen and a C1-6 alkyl group), for example, a 4oxazolylmethyl group , 5-oxazolylmethyl group, 2-methyl-4-oxazolylmethyl group, 2-methyl-5oxazolylmethyl group, 2,5-dimethyl-4-oxazolylmethyl group, 2,5-diphenyl-4-oxazolylmethyl group, 2,4-dimethyl group -5-oxazolylmethyl, 2-methyl-5-phenyl-4-oxazolylmethyl group, 2-methyl4-phenyl-5-oxazolylmethyl group, 2-phenyl-4-oxazolylmethyl group, 2-phenyl-5-oxazolylmethyl group, group 2- phenyl-5-methyl-4-oxazolylmethyl, 2-phenyl-4-methyl-5-oxazolylmethyl group, 2methyl-5- (2,3,4,5,6-pentafluorophenyl) -4-oxazolylmethyl group, 2-methyl group - 4- (2-fluorophenyl) -5Petition 870190039560, of 26/04/2019, p. 228/876

220/854 oxazolylmethyl, group 2- (2,4-difluorophenyl) -4-oxazolylmethyl, group 2- (2-fluorophenyl) -5oxazolylmethyl, group 2- (2-fluorophenyl) -5-methyl-4-oxazolylmethyl, group 2 - (2-fluorophenyl) 4-methyl-5-oxazolylmethyl, 2-methyl-5- (3-fluorophenyl) -4-oxazolylmethyl, group 2-methyl4- (3-fluorophenyl) -5-oxazolylmethyl, group 2- ( 3-fluorophenyl) -4-oxazolylmethyl, group 2- (3-fluorophenyl) -5-oxazolylmethyl, group 2- (3-fluorophenyl) -5-methyl-4-oxazolylmethyl, group 2 (3-fluorophenyl) -4-methyl-5 -oxazolylmethyl, 2-methyl-5- (4-fluorophenyl) -4-oxazolylmethyl group, 2-methyl-4- (4-fluorophenyl) -5-oxazolylmethyl group, 2- (4-fluorophenyl) -4-oxazolylmethyl group, group 2- (4-fluorophenyl) -5-oxazolylmethyl, group 2- (4-fluorophenyl) -5-methyl-4-oxazolylmethyl, group 2- (4-bromophenyl) -4-methyl-5-oxazolylmethyl, group 2- methyl-5- (2-chlorophenyl) -4oxazolylmethyl, 2-methyl-4- (2-chlorophenyl) -5-oxazolylmethyl group, 2- (2-chlorophenyl) -4oxazolylmethyl group, group 2- (2-iodophenyl) -5 -oxazolylmethyl, group 2- (2-chlorophenyl) -5-methyl-4oxazolylmethyl, g group 2- (2-chlorophenyl) -4-methyl-5-oxazolylmethyl, 2-methyl-5- (3chlorophenyl) -4-oxazolylmethyl group, 2-methyl-4- (3-chlorophenyl) -5-oxazolylmethyl group 2- (3-chlorophenyl) -4-oxazolylmethyl, group 2- (2,4,6-trichlorophenyl) -5-oxazolylmethyl, group 2- (3-chlorophenyl) -5-methyl-4-oxazolylmethyl, group 2- (3-chlorophenyl) -4-methyl-5-oxazolylmethyl, 2-methyl-5- (4-chlorophenyl) -4-oxazolylmethyl group, 2-methyl-4- (4-chlorophenyl) -5oxazolylmethyl group, group 2- (4-chlorophenyl) - 4-oxazolylmethyl, group 2- (4-chlorophenyl) -5oxazolylmethyl, group 2- (4-chlorophenyl) -5-methyl-4-oxazolylmethyl, group 2- (4-chlorophenyl) -4methyl-5-oxazolylmethyl, group 2- (4-oxazolyl) ethyl, group 2- (5-oxazolyl) ethyl, group 2- (2-methyl-4-oxazolyl) ethyl, group 2- (2-methyl-5-oxazolyl) ethyl, group 2- (2-phenyl -5-methyl-4oxazolyl) ethyl, group 2- [2- (4-chlorophenyl) -5-methyl-4-oxazolyl] ethyl, group 3- (4oxazolyl) propyl, group 3- (5-oxazolyl) propyl, group 3- (2-methyl-4-oxazolyl) propyl, group

3- (2-methyl-5-oxazolyl) propyl, group 3- (2-phenyl-5-methyl-4-oxazolyl) propyl, group 3- [2- (4chlorophenyl) -5-methyl-4-oxazolyl] propyl , group 4- (4-oxazolyl) butyl, group 4- (5oxazolyl) butyl, group 4- (2-methyl-4-oxazolyl) butyl, group 4- (2-methyl-5-oxazolyl) butyl, group 4- (2-phenyl-5-methyl-4-oxazolyl) butyl, group 4- [2- (4-chlorophenyl) -5-methyl-4oxazolyl] butyl, group 5- (4-oxazolyl) pentyl, group 5- (5 -oxazolyl) pentyl, group 5- (2-methyl-

4- oxazolyl) pentyl, group 5- (2-methyl-5-oxazolyl) pentyl, group 5- (2-phenyl-5-methyl-4oxazolyl) pentyl, group 5- [2- (4-chlorophenyl) -5- methyl-4-oxazolyl] pentyl, group 6- (4oxazolyl) hexyl, group 6- (5-oxazolyl) hexyl, group 6- (2-methyl-4-oxazolyl) hexyl, group 6

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221/854 (2-methyl-5-oxazolyl) hexyl, group 6- (2-phenyl-5-methyl-4-oxazolyl) hexyl, group 6- [2- (4-chlorophenyl) -6-methyl-4-oxazolyl] hexyl or similar.

[0296] Examples of an indolyl C1-6 alkyl group include an indolin-1ylmethyl group, indolin-2-ylmethyl group, indolin-3-ylmethyl group, indolin-4-ylmethyl group, indolin-5-ylmethyl group, indolin- 6-ylmethyl, indolin-7-ylmethyl group, group 2- (indolin-3yl) ethyl, group 3- (indolin-3-yl) propyl, group 4- (indolin-3-yl) butyl, group 5- (indolin -3yl) pentyl, group 6- (indolin-3-yl) hexyl, group 2- (indolin-4-yl) ethyl, group 3- (indolin-4il) propyl, group 4- (indolin-4-yl) butyl , group 5- (indolin-4-yl) pentyl, group 6- (indolin-4yl) hexyl, group 2- (indolin-5-yl) ethyl, group 3- (indolin-5-yl) propyl, group 4- (indolin-5yl) butyl, group 5- (indolin-5-yl) pentyl, group 6- (indolin-5-yl) hexyl, group 2- (indolin-6yl) ethyl, group 3- (indolin-6-yl ) propyl, group 4- (indolin-6-yl) butyl, group 5- (indolin-6yl) pentyl, group 6- (indolin-6-yl) hexyl, group 2- (indolin-7-yl) ethyl, group 3- (indolin-7yl) propyl, group 4- (indolin-7-yl) butyl, group 5- (indolin-7-yl) pentyl, group 6- (indolin-7yl) hexyl or similar.

[0297] A C1-6 furyl alkyl group (which can be substituted on the furan ring by at least one unsubstituted or halogen substituted phenyl group) includes a C1-6 furyl alkyl group (which can be substituted on the furan ring by 1 to 3 phenyl group unsubstituted or substituted by halogens), for example, a 2-furylmethyl group,

1- (3-furyl) ethyl, group 2- (2-furyl) ethyl, group 3- (3-furyl) propyl, group 4- (3-furyl) butyl, group 5- (2-furyl) pentyl, group 6- (2-furyl) hexyl, 2-methyl-3- (3-furyl) propyl group, 1,1-dimethyl-2- (2-furyl) ethyl group, 3,4-diphenyl-2-furylmethyl group, group 3,4,5-triphenyl-2-furylmethyl, group 5-phenyl-2-furylmethyl, group 5- (2-fluorophenyl) -2-furylmethyl, group 5- (3-fluorophenyl) -2-furylmethyl, group 5- (4- fluorophenyl) -2-furylmethyl, group 5- (2-chlorophenyl) -2furylmethyl, group 5- (3-chlorophenyl-2-furylmethyl, group 5- (4-chlorophenyl) -2-furylmethyl, group

5- (2-bromophenyl) -2-furylmethyl, group 5- (3-bromophenyl) -2-furylmethyl, group 5- (4bromophenyl) -2-furylmethyl, group 4-phenyl-2-furylmethyl, group 4- (2 , 3,4,5,6pentafluorophenyl) -2-furylmethyl, group 4- (3,4-difluorophenyl) -2-furylmethyl, group 4- (4iodophenyl) -2-furylmethyl, group 4- (2,3-dichlorophenyl- 2-furylmethyl, group 4- (3-chlorophenyl) -2 furimethyl, group 4- (2,4,6-trichlorophenyl) -2-funlmethyl, group 4- (2-bromophenyl-2-furylmethyl, group 4- (3- bromophenyl) -2-furylmethyl, group 4- (4-bromophenyl) -2-furylmethyl, group 5-phenyl-

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222/854

2-furylmethyl, group 2- (2-furyl) ethyl, group 3- (2-furyl) propyl, group 4- (2-furyl) butyl, group

5- (2-furyl) pentyl, group 6- (2-furyl) hexyl, group 2- [5- (4-chlorophenyl) -2-furyl] ethyl, group 3 [5- (4-chlorophenyl) -2- furyl] propyl, group 4- [5- (4-chlorophenyl) -2-furyl] butyl, group 5- (2-furyl) pentyl, group 6- [5- (4-chlorophenyl) -2-furyl] hexyl or the like.

[0298] An imidazolyl C1-6 alkyl group (which can be substituted on the imidazole ring by a phenyl group) includes an imidazolyl C1-6 alkyl group (which can be substituted on the imidazole ring by 1 to 2 phenyl groups), for example , a 4-imidazolylmethyl group, 2- (4-imidazolyl) ethyl group, 3- (2-imidazolyl) propyl group, 4- (1-imidazolyl) butyl group, 5- (5-imidazolyl) pentyl group, group 6 - (4-imidazolyl) hexyl, 2,5-diphenyl-1imidazolylmethyl group, 2-phenyl-4-imidazolylmethyl group, 2- (2-phenyl-4-imidazolyl) ethyl group, group 3- (2-phenyl-4- imidazolyl) propyl, group 4- (2-phenyl-5-imidazolyl) butyl, group 5- (2-phenyl-4-imidazolyl) pentyl, group 6- (2-phenyl-4-imidazolyl) hexyl or similar.

[0299] Examples of a C 1-6 quinolyl alkyl group include a 4quinolylmethyl group, 2- (4-quinolyl) ethyl group, 3- (4-quinolyl) propyl group, 4- (4quinolyl) butyl group, group 5- (4 -quinolyl) pentyl, group 6- (4-quinolyl) hexyl, group 5quinolylmethyl, group 2- (5-quinolyl) ethyl, group 3- (5-quinolyl) propyl, group 4- (5quinolyl) butyl, group 5- ( 5-quinolyl) pentyl, group 6- (5-quinolyl) hexyl, group 6quinolylmethyl, group 2- (6-quinolyl) ethyl, group 3- (6-quinolyl) propyl, group 4- (6quinolyl) butyl, group 5- (6-quinolyl) pentyl, group 6- (6-quinolyl) hexyl, group 7quinolylmethyl, group 2- (7-quinolyl) ethyl, group 3- (7-quinolyl) propyl, group 4- (7quinolyl) butyl, group 5 - (7-quinolyl) pentyl, group 6- (7-quinolyl) hexyl, group 8quinolylmethyl, group 2- (8-quinolyl) ethyl, group 3- (8-quinolyl) propyl, group 4- (8quinolyl) butyl, group 5- (8-quinolyl) pentyl, group 6- (8-quinolyl) hexyl or the like.

[0300] Examples of a tetrazolyl group (which can be substituted on the tetrazole ring by a phenyl group) include a 5- (1 H) -tetrazolyl group and a 1-pheni 1-5- (1H) tetrazolyl group.

[0301] Examples of a pyrimidyl group that can be substituted by a phenyl group include a 2-pyrimidyl group, 3-pyrimidyl group, 4-pyrimidyl group, 4-phenyl-2-pyrimidyl group, 2-phenyl-4-pyrimidyl group, group 4,6-diphenyl-2-pyrimidyl or the like.

[0302] Examples of a benzoxazolyl group include a 2-benzoxazolyl group,

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223/854 group 4-benzoxazolyl, group 5-benzoxazolyl, group 6-benzoxazolyl, group 7benzoxazolyl or the like.

[0303] Examples of a benzothiazolyl group include a benzothiazol-2-yl group, benzothiazol-4-yl group, benzothiazol-5-yl, benzothiazol-6-yl group, benzothiazole-

7-ila or similar.

[0304] A phenoxy C2-6 alkanoyl group that can be substituted on the phenyl ring by a halogen atom includes a phenoxy C2-6 alkanoyl group that can be substituted on the phenyl ring by 1 to 5 halogen atoms, for example, a phenoxyacetyl group, 3-phenoxypropionyl group, 4-phenoxybutyl group, 5-phenoxypentanoyl group, 6-phenoxyoxyanoyl group, 4- (4-chlorophenoxy) butyryl group, group 5- (4-chlorophenoxy) pentanoyl, group 6- (4-chlorophenoxy) hexaneyl , group 2-fluorophenoxyacetyl, group 3-fluorophenoxyacetyl, group 4-fluorophenoxyacetyl, group 2-chlorophenoxyacetyl, group 3-chlorophenoxyacetyl, group 4-chlorophenoxyacetyl, group 4-bromophenoxyacetyl, group 2,3-

difluorophenoxyacetyl, group 2-fluoro-4-chlorophenoxyacetyl, group 3.5- difluorophenoxyacetyl, group í 2,3,4,5,6-pentafluorophenoxyacetyl, group 2.4.6- trichlorophenoxyacetyl, group 3- (2-fluorophenoxy) propionyl, group 3- (3- fluorophenoxy) propionyl, group 3- (4-fluorophenoxy) propionyl, group 3- (2- chlorophenoxy) propionyl, group 3- (3-chlorophenoxy) propionyl, group 3- (4- chlorophenoxy) propionyl, group 3- (4-bromophenoxy) propionyl, group 3- (2,3- difluorophenoxy) propionyl, group 3- (2-fluoro-4-chlorophenoxy) propionyl, group 3- (3.5-

difluorophenoxy) propionyl or the like.

[0305] A C2-6 alkanoyl phenylthio group that can be substituted by a halogen atom is a group containing from 1 to 5 unsubstituted or substituted phenylthio groups from 1 to 5 halogens and a C1-6 alkanoyl group, examples being of these include a phenylthioacetyl group, 3-phenylthiopropionyl group, 4-phenylthiobutyryl group, 5-phenylthiopentanoyl group, 6-phenylthioexanoyl group, 4- (4-chlorophenyl) -thiobutyryl group, 5- (4-chlorophenyl) thiopentanyl group, group 6- (4) thioexanoyl, 2-fluorophenylthioacetyl group, 3-fluorophenylthioacetyl group, 4-fluorophenylthioacetyl group, 2-chlorophenylthioacetyl group, 2,4-dichlorophenylthioacetyl group, 2,4,6-trichlorophenylthioacetyl group, 2,3,4,5,6,6-pentafluent , group 3

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224/854 chlorophenylthioacetyl, group 4-chlorophenylthioacetyl, group 4-bromophenylthioacetyl, group 2,3difluorophenylthioacetyl, group 2-fluoro-4-chlorophenylthioacetyl, group 3,5difluorophenylthioacetyl, group 3- (2-fluorophenyl) fluorophenyl) thiopropionyl, group 3- (4-fluorophenyl) thiopropionyl, group 3- (2-chlorophenyl) thiopropionyl, group 3- (3-chlorophenyl) thiopropionyl, group 3- (4-chlorophenyl) -thiopropionyl, group 3- (4bromophenyl) ) thiopropionyl, group 3- (2,3-difluorophenyl) thiopropionyl, group 3- (2-fluoro-4chlorophenyl) thiopropionyl, group 3- (3,5-difluorophenyl) thiopropionyl or the like.

[0306] A benzoyl group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group, unsubstituted C1-6 alkoxy group or substituted by halogen and amino group which may have a C1-6 alkyl group as a substituent) include a benzoyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group that consists of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen and amino group which may have 1 to 2 C1-6 alkyl groups as a substituent), for example, a benzoyl group, 2-fluorobenzoyl group

3-fluorobenzoyl, 4-fluorobenzoyl group, 2,3-difluorobenzoyl group, 3,4difluorobenzoyl group, 2-chlorobenzoyl group, 3-chlorobenzoyl group, 4-chlorobenzoyl group, 2,3-dichlorobenzoyl group, 3,4-dichlorobenzoyl group, 2,4,6-trichlorobenzoyl group, 4-iodobenzoyl group, 2,3,4,5,6-pentafluorobenzoyl group, 2-bromobenzoyl group, 3-bromobenzoyl group, 4-bromobenzoyl group, 2,3-dibromobenzoyl group, group 3,4-dibromobenzoyl, 2-methylbenzoyl group, 3-methylbenzoyl group, 4methylbenzoyl group, 2,3-dimethylbenzoyl group, 3,4-dimethylbenzoyl group, 3,4,5trimethylbenzoyl group, 2-trifluoromethyl benzoyl group, 3-trifluoromethylbenzyl group, 3-trifluoromethyl group 4trifluoromethylbenzoyl group, 2,3-ditrifluoromethylbenzoyl group, 3,4ditrifluoromethylbenzoyl group, 2-methoxybenzoyl group, 3-methoxybenzoyl group, 4methoxybenzoyl group, 3,4-dimethoxybenzoyl group, 2,4,6-trimethoxy benzyl group, 3trififenz group trifluoromethoxybenzoyl, group 4trifluoromethoxy ibenzoyl, group 2-aminobenzoyl, group 3-aminobenzoyl, group 4

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225/854 aminobenzoyl, 2-methylaminobenzoyl group, 3-methylaminobenzoyl group, 4methylaminobenzoyl group, 2-ethylaminobenzoyl group, 3-ethylaminobenzoyl group, 4ethylaminobenzoyl group, 2-propylaminobenzyl group, 3-propylaminobenzyl group, 3-propylaminobenzyl group,

4-propylaminobenzoyl, 4-butylaminobenzoyl group, 4-pentylaminobenzoyl group, 4-hexylaminobenzoyl group, 2-dimethylaminobenzoyl group, 3dimethylaminobenzoyl group, 4-dimethylaminobenzoyl group, 2-diethylaminobenzoyl group, 3-diethylaminyl group, 3-diethylaminyl group 3-dipropylaminobenzoyl group, 4-dipropylaminobenzoyl group, 4-dibutylaminobenzoyl group, 4-dipentylaminobenzoyl group, 4diexylaminobenzoyl group or the like.

[0307] Examples of a biphenylylcaronyl group include a 2-biphenylylcaronyl group, 3-biphenylylcaronyl group, 4-biphenylylcaronyl group or the like.

[0308] Examples of a pyridylcarbonyl group include a 2-pyridylcarbonyl group, 3-pyridylcarbonyl group, 4-pyridylcarbonyl group or the like.

[0309] Examples of a phenyl C2-6 alkenyloxycarbonyl group that can be substituted on the phenyl ring by a halogen atom include a phenyl C2-6 alkenyloxycarbonyl group that can be substituted on the phenyl ring by 1 to 5 halogen atoms, for example , a 3-phenyl-2-propenylcarbonyl group (common name: cinnamoyl group), 4-phenyl-2-butenylcarbonyl group, 4-phenyl-3-butenylcarbonyl group, 5-phenyl-2-pentenylcarbonyl group, 5-phenyl-4- group pentenylcarbonyl, 5-phenyl-3pentenylcarbonyl group, 6-phenyl-5-hexenylcarbonyl group, 6-phenyl-4-pentenylcarbonyl group, 6-phenyl-3-hexenylcarbonyl group, 4-phenyl-1,3-butadienylcarbonyl group, group 6- phenyl-

1,3,5-hexathrienylcarbonyl, group 3- (2-fluorophenyl) -2-propenylcarbonyl (also referred to as a common name 2-fluorokinamoyl group), group 3- (3-fluorophenyl) -2propenylcarbonyl, group 3- (4 -fluorophenyl) -2-propenylcarbonyl, group 2,4difluorokinamoyl, group 3- (2,5-difluorophenyl) -2-propenylcarbonyl, group 3- (3,5difluorophenyl) -2-propenylcarbonyl, group 3- (3,4-difluorophenyl ) -2-propenylcarbonyl, group 3- (2,3,4,5,6-pentafluorophenyl) -2-propenylcarbonyl, group 3- (2-chlorophenyl) -2propenylcarbonyl, group 3- (3-chlorophenyl) -2-propenylcarbonyl , group 3- (4-chlorophenyl) -2propenylcarbonyl, group 3- (2,4-dichlorophenyl) -2-propenylcarbonyl, group 3- (2,5

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226/854 dichlorophenyl) -2-propenylcarbonyl, group 3- (3,5-dichlorophenyl) -2-propenylcarbonyl, group 3- (3,4-dichlorophenyl) -2-propenylcarbonyl, group 3- (2,4,6- trichlorophenyl) -2propenylcarbonyl, group 3- (2-bromophenyl) -2-propenylcarbonyl, group 3- (3-bromophenyl) -

2-propenylcarbonyl, group 3- (4-bromophenyl) -2-propenylcarbonyl, group 3- (2,4dibromophenyl) -2-propenylcarbonyl, group 3- (2,5-dibromophenyl) -2-propenylcarbonyl, group 3- (3 , 5-dibromophenyl) -2-propenylcarbonyl, group 3- (3,4-dibromophenyl) -2propenylcarbonyl or the like.

[0310] A phenyl C1-6 alkylsulfonyl group that can be substituted on the phenyl ring by halogen atoms is a group that contains a phenyl C1-6 alkyl group that can be substituted on the phenyl ring by 1 to 5 halogen atoms, as defined above, and a sulfonyl group, examples of which include a benzylsulfonyl group, phenethylsulfonyl group, 3-phenylpropylsulfonyl group, 4-phenylbutylsulfonyl group, 5-phenylpentylsulfonyl group, 6-phenylexylsulfonyl group, 2-fluorobenzylsulfonyl group, 4-flu-group fluorobenzylsulfonyl, group 2-chlorobenzylsulfonyl, group 3-chlorobenzylsulfonyl, group 4-chlorobenzylsulfonyl, group

2,3-dichlorobenzylsulfonyl, 3,4-dichlorobenzylsulfonyl group, group 3.5- dichlorobenzylsulfonyl, group 2,4-dichlorobenzylsulfonyl, group 3.4.5- trifluorobenzylsulfonyl,, group 2,3,4,5,6-pentafluorobenzylsulfonyl, group 2- (2- fluoro) phenethylsulfonyl, group 2- (3-fluoro) phenethylsulfonyl, group 2- (4- fluoro) phenethylsulfonyl, group 2- (2-chloro) phenethylsulfonyl, group 2- (3- chlorine) phenethylsulfonyl, group 2- (4-chloro) phenethylsulfonyl, group 2- (2,3- dichloro) phenethylsulfonyl, group 2- (3,4-dichloro) phenethylsulfonyl, group 2- (3.5- dichloro) phenethylsulfonyl, group 2- (2,4-dichloro) phenethylsulfonyl, group 2 - (3,4,5- trifluoro) phenethylsulfonyl, group 3- (2-fluorophenyl) propylsulfonyl, group 3- (3- fluorophenyl) propylsulfonyl, group 3- (4-fluorophenyl) propylsulfonyl, group 3- (2-

chlorophenyl) propylsulfonyl, group 3- (3-chlorophenyl) propylsulfonyl, group 3- (4-chlorophenyl) propylsulfonyl, group 2- (2,3-dichlorophenyl) propylsulfonyl, group 3- (3,4dichlorophenyl) propylsulfonyl, group 3- ( 3,5-dichlorophenyl) propylsulfonyl, group 3- (2,4dichlorophenyl) propylsulfonyl, group 3- (3,4,5-trifluorophenyl) propylsulfonyl or the like.

[0311] A Ci-e alkyl group unsubstituted or substituted by halogen includes

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227/854 a C1-8 alkyl group unsubstituted or substituted by 1-7 halogen atoms, for example, a methyl group, ethyl group, n-propyl group, isopropyl group, nbutyl group, isobutyl group, ter-butyl group , sec- [gap] group, n-pentyl group, neopentyl group, 3-methylpentyl group, n-hexyl group, isohexyl group, 1,3,5-trimethylhexyl group, n-heptyl group, 6-methylpile group, 1-methylpile group , n-octyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl, dichlorofluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 2-chloroethyl group , 3,3-trifluoropropyl, heptafluoropropyl group, heptafluoroisopropyl group, 3-chloropropyl group, 2-chloropropyl group, 3-bromopropyl group, 4,4,4trifluorobutyl group, 4,4,4,3,3-pentafluorobutyl group, group 4 -chlorobutyl, group 4bromobutyl, group 2-chlorobutyl, group 5,5,5-trifluoropentyl, group o 5-chloropentyl, group 6,6,6-trifluoroexyl, group 6-chlorohexyl, group 7-chloroeptyl, group 8-chlorooctyl or the like.

[0312] An amino C1-6 alkyl group that may have a C1-6 alkyl group include an amino C1-6 alkyl group that may have 1 to 2 C1-6 alkyl groups, for example, an aminomethyl group, group 2- aminoethyl, group 1-aminoethyl, group

3-aminopropyl, 4-aminobutyl group, 5-aminopentyl group, 6-aminoexyl group, group

2-methyl-3-aminopropyl, 1,1-dimethyl-2-aminoethyl group, ethylaminomethyl group, group 1 (propylamino) ethyl, group 2- (methylamino) ethyl, group 3- (isopropylamino) propyl, group 4 (n- butylamino) butyl, group 5- (n-pentylamino) pentyl, group 6- (n-hexylamino) hexyl, dimethylaminomethyl group, group (N-methyl-N-propylamino) methyl, group 2- (N-methyl-Nhexylamino) ethyl or similar.

[0313] Examples of a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 5 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen, C1-6 alkylthio group unsubstituted or substituted by halogen, phenyl C1-6 alkoxy group, hydroxy group, C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, C1- group 6 sulfonyloxy alkyl, cyano group, C1-6 alkanoyl group, benzoyl group, phenyl C1-6 alkyl group (which may have a

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228/854 C1-6 alkoxy group on the alkyl portion), amino group, nitro group, carbamoyl group, C1-6 alkanoylamino group, C1-6 alkoxycarbonyl group, C1-6 alkylaminocarbonyl group, C1-6 alkoxycarbonylamino group, C1 tri alkylsilyloxy group -6, pyrrolyl group, tetrahydropyranyloxy group and imidazolyl group) include a benzyl group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 4-phenylpentyl group, group 6-phenylexyl, group 2-fluorobenzyl, group 3-fluorobenzyl, group 4-fluorobenzyl, group 2-chlorobenzyl, group 3-chlorobenzyl, group 4-chlorobenzyl, group 2-bromobenzyl, group 3-bromobenzyl, group 4-2-bromobenzyl, group 4 -iodobenzyl, 3-iodobenzyl group, 4-iodobenzyl group, 2,3difluorobenzyl group, 3,4-difluorobenzyl group, 3,5-difluorobenzyl group, 2,3,4,5,6 pentafluorobenzyl group, 2,4-difluorobenzyl group, group 2,6-difluorobenzyl, 2,4,6trifluorobenzyl, group 3,4,5-trifluorobenzyl, group 2,3-dichloro benzyl, 3,4dichlorobenzyl group, 3,5-dichlorobenzyl group, 2,4-dichlorobenzyl group, 2,6dichlorobenzyl group, 2,4,6-trichlorobenzyl group, 3,4,5-trichlorobenzyl group, perfluorobenzyl group, 2-difluoromethyl benzyl group , 3-difluoromethylbenzyl group, 4difluoromethylbenzyl group, 4-chloro-3-difluoromethylbenzyl group, 3-chloro-4difluoromethylbenzyl group, 3-bromo-4-difluoromethylbenzyl group, 3,5-difluoro-4difluorylbenzyl group -methylbenzyl, 4-methylbenzyl group, 2,3-dimethylbenzyl group, 2,4,6-trimethylbenzyl group, 3,5-ditrifluoromethylbenzyl group, 2-trifluoromethylbenzyl group, 3-trifluoromethylbenzyl group, 4trifluoromethylbenzyl group -trifluoromethylbenzyl, 3-fluoro-4trifluoromethylbenzyl group, 2-pentafluoroethylbenzyl, 4-chloro-3-pentafluoroethylbenzyl group, 3-chloro-4-pentafluoroethylbenzyl, 2-pentafluoroethylbenzyl group, 2-pentafluoroethylbenzyl group, 2-pentafluoroethylbenzyl group 3metoxibenzi group la, 4-methoxybenzyl group, 2,3-dimethoxybenzyl group, 2,4,6-trimethoxybenzyl group, 3,5-ditrifluoromethoxybenzyl group, 2-trifluoromethoxybenzyl group, 3-trifluoromethoxybenzyl group, 4-trifluoromethoxybenzyl group, 4-fluoro-trifluoro group pentafluoroetoxibenzila, pentafluoroetoxibenzila, group 3-fluoro-4-trifluoromethoxybenzyl, group 2group 3-pentafluoroethoxybenzyl, group 4group 3-chloro-4-trifluoromethoxybenzyl, group 3-chloro-4Petição 8701900395, pág. 237/876

229/854

pentafluoroethoxybenzyl, group 2- (2-trifluoromethylphenyl) ethyl, group 2- (3- trifluoromethylphenyl) ethyl, group 2- (4-trifluoromethylphenyl) ethyl, group 2- trifluoromethoxyphenyl) ethyl, group 3-trifluoromethoxyphenyl) ethyl, group 2- (3- trifluoromethoxyphenyl) ethyl, group 2- (2-pentafluoroethoxyphenyl) ethyl, group 2- (3- pentafluoroethoxyphenyl) ethyl, group 2- (4-pentafluoroethoxyphenyl) ethyl, group 3- (2- trifluoromethylphenyl) propyl, group 3- (3-trifluoromethylphenyl) propyl, group 3- (4- trifluoromethylphenyl) propyl, group 3- (2-trifluoromethoxyphenyl) propyl, group 3- (3- trifluoromethoxyphenyl) propyl, group 3- (4-trifluoromethoxyphenyl) propyl, group 3- (3- pentafluoroethoxyphenyl) propyl, group 3- (4-pentafluoroethoxyphenyl) propyl, group 4- (3- pentafluoroethoxyphenyl) butyl, group 5- (4-trifluoromethylphenyl) pentyl, group 4- (4- trifluoromethylphenyl) pentyl, group 4- (4-trifluoromethoxyphenyl) pentyl, group 6- (3- trifluoromethylphenyl) hexyl, group 6- (4-trifluoromethylphenyl) hexyl, group 6- (4-

trifluoromethoxyphenyl) hexyl, 2-methylthiobenzyl group, 3-methylthiobenzyl group, 4methylthiobenzyl group, 2,3-dimethylthiobenzyl group, 2,4,6-trimethylthiobenzyl group, 2- (2 methylthiophenyl) ethyl group, 2- (3-methylthiophenyl) group ethyl, group 2- (4-methylthiophenyl) ethyl, group 3- (4-methylthiophenyl) propyl, group 4- (4-methylthiophenyl) butyl, group 5- (4-methylthiophenyl) pentyl,

group 6- (4-methylthiophenyl) hexyl, 2-trifluoromethylthiobenzyl group, group 3- trifluoromethylthiobenzyl, group 4-trifluoromethylthiobenzyl, group 2- (2- trifluoromethylthiophenyl) ethyl, group 2- (3-trifluoromethylthiophenyl) ethyl, group 2- (4- trifluoromethylthiophenyl) ethyl, group 3- (4-trifluoromethylthiophenyl) propyl, group 4- (4- trifluoromethylthiophenyl) butyl, group 5- (4-trifluoromethylthiophenyl) pentyl, group 6- (4-

trifluoromethylthiophenyl) hexyl, group 2-benzyloxybenzyl, group 3-benzyloxybenzyl, group

4-benzyloxybenzyl, group 2- (2-benzyloxyphenyl) ethyl, group 2- (3-benzyloxyphenyl) ethyl, group 2- (4-benzyloxyphenyl) ethyl, group 3- (4-benzyloxyphenyl) propyl, group 4- (4benzyloxyphenyl) butyl, group 5- (4-benzyloxyphenyl) pentyl, group 6- (4-benzyloxyphenyl) hexyl, group 2- (2-phenyloxy) benzyl, group 3- (2-phenyloxy) benzyl, group 4- (2-phenyloxy) benzyl, group 2- [2- (2-phenylethoxyphenyl)] ethyl, group 2- [3- (2-phenylethoxyphenyl)] ethyl, group 2- [4- (2-phenylethoxyphenyl)] ethyl, group 3- [4- (2 -phenylethoxyphenyl)] propyl, group 4- [4- (2-phenylethoxyphenyl)] butyl, group 5- [4- (2-phenylethoxyphenyl)] pentyl, group 6- [4- (2-phenylethoxyphenyl)] hexyl, group 2- (3- phenylpropoxy) benzyl, group 3- (3-phenylpropoxy) benzyl,

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230/854 group 4- (3-phenylpropoxy) benzyl, group 2- (4-phenylbutoxy) benzyl, group 3- (4-phenylbutoxy) benzyl, group 4- (4-phenylbutoxy) benzyl, group 2-methoxycarbonylbenzyl,

3-methoxycarbonylbenzyl group, 4-methoxycarbonylbenzyl group, group 2- (2- methoxycarbonylphenyl) ethyl, group 2- (3-methoxycarbonylphenyl) ethyl, group 2- (4- methoxycarbonylphenyl) ethyl, group 3- (4-methoxycarbonylphenyl) propyl, group 4- (4- methoxycarbonylphenyl) butyl, group 5- (4-methoxycarbonylphenyl) pentyl, group 6- (4-

methoxycarbonylphenyl) hexyl, 2-hydroxybenzyl group, 3-hydroxybenzyl group, 4-hydroxybenzyl group, 2,3-dihydroxybenzyl group, 2,4,6-trihydroxybenzyl group, 2- (2-hydroxyphenyl) ethyl group, 2- (3-hydroxyphenyl) ethyl group , 2- (4-hydroxyphenyl) ethyl group, 3- (4-hydroxyphenyl) propyl group, 4- (4-hydroxyphenyl) butyl group, 5- (4-hydroxyphenyl) pentyl group, group

6- (4-hydroxyphenyl) hexyl, 2-methylsulfinylbenzyl group, 3-methylsulfinylbenzyl group, 4-methylsulfinylbenzyl group, 2,3-dimethylsulfinylbenzyl group, 2,4,6-trimethylsulfinylbenzyl group,

2- (2-methylsulfinylphenyl) ethyl group, 2- (3-methylsulfinylphenyl) ethyl group, group 2- (4- methylsulfinylphenyl) ethyl, group 3- (4-methylsulfinylphenyl) propyl, group 4- (4- methylsulfinylphenyl) butyl, group 5- (4-methylsulfinylphenyl) pentyl, group 6- (4- methylsulfinylphenyl) hexyl, group 2-methanesulfonylbenzyl, group 3- methanesulfonylbenzyl, group 4-methanesulfonylbenzyl, group 2.3- dimethanesulfonylbenzyl, group 2,4,6-trimethanesulfonylbenzyl, group 2- (2- methanesulfonylphenyl) ethyl, group 2- (3-methanesulfonylphenyl) ethyl, group 2- (4- methanesulfonylphenyl) ethyl, group 3- (4-methanesulfonylphenyl) propyl, group 4- (4- methanesulfonylphenyl) butyl, group 5- (4-methanesulfonylphenyl) pentyl, group 6- (4- methanesulfonylphenyl) hexyl, 2-methanesulfonyloxybenzyl group, group 3- methanesulfonyloxybenzyl, group 4-methanesulfonyloxybenzyl, group 2.3- dimethanesulfonyloxybenzyl, group 2,4,6-trimethanesulfonyloxybenzyl, group 2- (2- methanesulfonyloxyphenyl) ethyl, group 2- (3-methanesulfonyloxyphenyl) ethyl, group 2- (4- methanesulfonyloxyphenyl) ethyl, group 3- (4-methanesulfonyloxyphenyl) propyl, group 4- (4-

methanesulfonyloxyphenyl) butyl, group 5- (4-methanesulfonyloxyphenyl) pentyl, group 6- (4methanesulfonyloxyphenyl) hexyl, group 2-cyanobenzyl, group 3-cyanobenzyl, group 4-cyanobenzyl, group 2,3-dicyobenzyl, group 2,4,6-trician , group 2- (2-cyanophenyl) ethyl, group 2- (3-cyanophenyl) ethyl, group 2- (4-cyanophenyl) ethyl, group 3- (4

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231/854 cyanophenyl) propyl, group 4- (4-cyanophenyl) butyl, group 5- (4-cyanophenyl) pentyl, group 6 (4-cyanophenyl) hexyl, group 2-acetylbenzyl, group 3-acetylbenzyl, group 4-acetylbenzyl , 2- (2-acetylphenyl) ethyl group, 2- (3-acetylphenyl) ethyl group, 2- (4-acetylphenyl) ethyl group, group

3- (4-acetylphenyl) propyl, group 4- (4-acetylphenyl) butyl, group 5- (4-acetylphenyl) pentyl, group

6- (4-acetylphenyl) hexyl, group 2-benzoyl benzyl, group 3-benzoyl benzyl, group 4 benzoyl benzyl, group 2- (2-benzoyl phenyl) ethyl, group 2- (3-benzoyl phenyl) ethyl, group 2- (4 benzoyl phenyl) ethyl, group 3- (4-benzoylphenyl) propyl, group 4- (4-benzoylphenyl) butyl, group

5- (4-benzoylphenyl) pentyl, group 6- (4-benzoylphenyl) hexyl, group 2-α, αdimethoxybenzylbenzyl, group 3-a, α-dimethoxybenzylbenzyl, group 4-α, αdimethoxybenzylbenzyl, group 2- (2-a, a-dimethoxybenzylphenyl) ethyl, group 2- (3- (α, αdimethoxybenzyl) phenyl) ethyl, group 2- (4- (a, a-dimethoxybenzyl) phenyl) ethyl, group 3- (4- (oc, oc dimethoxybenzyl) phenyl) propyl, group 4- (4- (a, a-dimethoxybenzyl) phenyl) butyl, group 5- (4 (a, a-dimethoxybenzyl) phenyl) pentyl, group 6- (4- (a, a-dimethoxybenzyl) phenyl) hexyl, group 2aminobenzyl, group 3-aminobenzyl, group 4-aminobenzyl, group 2,3diaminobenzyl, group 2,4,6-triaminobenzyl, group 2- (2-aminophenyl) ethyl, group 2- (3aminophenyl) ethyl, group 2- (4-aminophenyl) ethyl, group 3- (4-aminophenyl) propyl, group 4- (4-aminophenyl) butyl, group 5- (4-aminophenyl) pentyl, group 6- (4-aminophenyl) hexyl, group 2nitrobenzyl, group 3-nitrobenzyl, group 4-nitrobenzyl, group 2,4-dinitrobenzyl, group

2,4,6-trinitrobenzyl, group 2- (2-nitrophenyl) ethyl, group 2- (3-nitrophenyl) ethyl, group 2- (4-nitrophenyl) ethyl, group 3- (4-nitrophenyl) propyl, group 4- ( 4-nitrophenyl) butyl, group 5- (4nitrophenyl) pentyl, group 6- (4-nitrophenyl) hexyl, group 2-carbamoyl benzyl, group 3carbamoyl benzyl, group 4-carbamoyl benzyl, group 2- (2-carbamoylphenyl) ethyl, group 2-

(3-carbamoylphenyl) ethyl, group 2- (4-carbamoylphenyl) ethyl, group 3- (4- carbamoylphenyl) propyl, group 4- (4-carbamoylphenyl) butyl, group 5- (4- carbamoylphenyl) pentyl, group 6- (4-carbamoylphenyl) hexyl, group 2-acetylaminobenzyl, 3-acetylaminobenzyl group, 4-acetylaminobenzyl group, group 2- (2- acetylaminophenyl) ethyl, group 2- (3-acetylaminophenyl) ethyl, group 2- (4- acetylaminophenyl) ethyl, group 3- (4-acetylaminophenyl) propyl, group 4- (4- acetylaminophenyl) butyl, group 5- (4-acetylaminophenyl) pentyl, group 6- (4-

acetylaminophenyl) hexyl, 2-ethoxycarbonylbenzyl group, 3-ethoxycarbonylbenzyl group,

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232/854 group 4-ethoxycarbonylbenzyl, group 2- (2-ethoxycarbonylphenyl) ethyl, group 2- (3ethoxycarbonylphenyl) ethyl, group 2- (4-ethoxycarbonylphenyl) ethyl, group 3- (4-

ethoxycarbonylphenyl) propyl, group 4- (4-ethoxycarbonylphenyl) butyl, group 5- (4- ethoxycarbonylphenyl) pentyl, group 6- (4-ethoxycarbonylphenyl) hexyl, group 2- methylaminocarbonylbenzyl, group 3-methylaminocarbonylbenzyl, group 4- methylaminocarbonylbenzyl, group 2-dimethylaminocarbonylbenzyl, group 3- dimethylaminocarbonylbenzyl, group 2-ethylaminocarbonylbenzyl, group 3- ethylaminocarbonylbenzyl, group 4-ethylaminocarbonylbenzyl, group 4- dimethylaminocarbonylbenzyl, group 2-diethylaminocarbonylbenzyl, group 3- diethylaminocarbonylbenzyl, group 4-diethylaminocarbonylbenzyl, group 2- (di-n-

propylaminocarbonyl) benzyl, group 3- (di-n-propylaminocarbonyl) benzyl, group 4- (di-n-

propylaminocarbonyl) benzyl, group 2-methoxycarbonylaminobenzyl, group 3- methoxycarbonylaminobenzyl, group 4-methoxycarbonylaminobenzyl, group 2- ethoxycarbonylaminobenzyl, group 3-ethoxycarbonylaminobenzyl, group 4-

ethoxycarbonylaminobenzyl, group 2- (tert-butoxycarbonylamino) benzyl, group 3- (terbutoxycarbonylamino) benzyl, group 4- (tert-butoxycarbonylamino) benzyl, group 4trimethylsiloxybenzyl, group 4-triethylsiloxybenzyl, group 2-pyrrolbenzyl, group 2-pyrrolbenzyl , group 2- (1-imidazolyl) benzyl, group 3- (1imidazolyl) benzyl, group 4- (1-imidazolyl) benzyl, group 2- (2-tetrahydropyranyloxy) benzyl, group 3- (2-tetrahydropyranyloxy) benzyl, group 4- (2-tetrahydropyranyloxy) benzyl or the like.

[0314] Example of a benzhydryl group (which can be substituted on the benzene ring by at least one group selected from a group consisting of a halogen atom, trifluoromethyl group and trifluoromethoxy group) includes a benzhydryl group, 4.4 ' -dichlorobenzhydryl, 4,4'-difluorobenzhydryl group, 4,4'ditrifluoromethylbenzhydryl group, 4,4'-ditrifluoromethoxybenzidyl group or the like.

[0315] A C2-6 phenyl alkynyl group (which may have at least one unsubstituted or halogen substituted C1-6 alkyl group as a substituent on the phenyl ring) includes a C2-6 phenyl alkynyl group (which may have from 1 to 3 C1-6 alkyl groups unsubstituted or substituted by halogen as a substituent on the phenyl ring),

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233/854 for example, 2-phenylethynyl group, 3-phenyl-2-propynyl group, 4-phenyl-3-butynyl group, 4-phenyl-2-butynyl group, 5-phenyl-4-pentynyl group, group 6- phenyl-5-hexynyl, 2methylphenyl-2-propynyl group, 3-methylphenyl-3-butynyl group, 4-methylphenyl-2-butynyl group, 2,4-dimethylphenyl-4-pentinyl group, 2,4,6-trimethylphenyl group -5-hexynyl, 3,5ditrifluoromethylphenyl-2-propynyl group, 2-trifluoromethylphenyl-3-butynyl group, 3trifluoromethylphenyl-2-butynyl group, 4-trifluoromethylphenyl-2-propynyl group or the like.

[0316] A C2-6 phenyl alkynyl group (which may have at least one unsubstituted or halogen substituted C1-6 alkyl group as a substituent on the phenyl ring) includes a C2-6 phenyl alkynyl group (which may have from 1 to 3 C1-6 alkyl groups unsubstituted or substituted by halogen as a substituent on the phenyl ring), for example, 2-phenylethynyl, 3-phenyl-2-propynyl group, 4-phenyl-3-butynyl group, 4-phenyl-2- group butynyl, 5-phenyl-4-pentynyl group, 6-phenyl-5-hexynyl group, 2-methylphenyl-2propynyl group, 3-methylphenyl-3-butynyl group, 4-methylphenyl-2-butynyl group, 2,4dimethylphenyl- 4-pentynyl, 2,4,6-trimethylphenyl-5-hexynyl group, 3,5ditrifluoromethylphenyl-2-propynyl group, 2-trifluoromethylphenyl-3-butynyl group, 3trifluoromethylphenyl-2-butynyl group, 4-trifluoromethylphenyl-2-propinyl group or similar.

[0317] Examples of a C1-6 alkyl pyridyl group include a 2-pyridylmethyl group, 2- (3-pyridyl) ethyl group, 1- (4-pyridyl) ethyl group, 3- (2-pyridyl) propyl group, group 4- (3pyridyl) butyl, group 5- (4-pyridyl) pentyl, group 6- (2-pyridyl) hexyl, group 2-methyl-3- (3pyridyl) propyl, group 1,1-dimethyl-2- (2 -pyridyl) ethyl or the like.

[0318] A C1-6 alkyl piperidine group (which can be substituted on the piperidine ring by at least one phenoxy group which can have at least one unsubstituted alkyl group or substituted by halogen as a substituent on the phenyl ring) includes a piperidine alkyl group C1-6 (which can be substituted on the piperidine ring by a phenoxy group which can have 1 to 3 unsubstituted alkyl group or substituted by halogens as a substituent on the phenyl ring), for example, piperidin-1-methylmethyl group, group 2 - (piperidin-2-yl) ethyl, group 3- (piperidin-3yl) propyl, group 4- (piperidin-4-yl) butyl, group 5- (piperidin-1-yl) pentyl, group 6 (piperidin-1 -yl) hexyl, 4- (4-trifluoromethylphenoxy) pipendin-1-ylmethyl group, 4-phenoxypiperidin-1-ylmethyl group, 4- (4-methylphenoxy) piperidin-1-ylmethyl group, group 4- (2,4

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234/854 d imethylphenoxy) piperid in-1-methylmethyl, group 4- (2,4,6-trim ethylphenoxy) piperid in-1-ylmethyl, group 2- [4- (4-trifluoromethylphenoxy) piperidin-1 -yl] ethyl, group 3- [4- (4trifluoromethylphenoxy) pipendin-1 -yl] propyl, group 4- [4- (4-trifluoromethylphenoxy) pipendin-1 yl] butyl, group 5- [4- (4-trifluoromethylphenoxy ) piperidin-1-yl] pentyl, group 6- [4- (4trifluoromethylphenoxy) pipendin-1-yl] hexyl or the like.

[0319] A C1-6 alkyl amino group that may have as a substituent at least one group selected from a group consisting of a C1-6 alkyl group and a phenyl group that may have an unsubstituted or substituted halogen C1-6 alkoxy group as a substituent on the phenyl ring includes a C1-6 alkyl amino group which may have as a substituent from 1 to 2 groups selected from a group consisting of a C1-6 alkyl group and a phenyl group which may have C1-6 alkoxy groups unsubstituted or substituted by 1 to 3 halogens as a substituent on the phenyl ring, for example, an aminomethyl group, 2aminoethyl group, 2-aminopropyl group, 3-aminopropyl group, 3-aminobutyl group, group

4-aminobutyl, 5-aminopentyl group, 6-aminohexyl group, 2-methylaminoethyl group, 2-methylaminopropyl group, 3-methylaminopropyl group, 3-methylaminobutyl group, 4-methylaminobutyl group, 5-methylaminopentyl group, 6-methylaminoexyl group, group

2- (ethylamino) ethyl, group 3- (ethylamino) propyl, group 4- (ethylamino) butyl, group 5 (ethylamino) pentyl, group 6- (ethylamino) hexyl, group 2- (n-propylamino) ethyl, group 3 - (npropylamino) propyl, group 4- (n-propylamino) butyl, group 5- (n-propylamino) pentyl, group 6- (n-propylamino) hexyl, group 2- (n-butylamino) ethyl, group 3- ( nbutilamino) propyl, group 2- (n-pentylamino) ethyl, group 3- (n-pentylamino) propyl, group

2- (n-hexylamino) ethyl, group 3- (n-hexylamino) propyl, group 2-dimethylaminoethyl, group

2- dimethylaminopropyl, 3-dimethylaminopropyl group, 3-dimethylaminobutyl group, 4-dimethylaminobutyl group, 5-dimethylaminopentyl group, 6-dimethylaminohexyl group, group 2 (diethylamino) ethyl, group 3- (diethylamino) propyl, group 4- (diethylamino) butyl, group 5 (diethylamino) pentyl, group 6- (diethylamino) hexyl, group 2- (di-n-propylamino) ethyl, group

3- (di-n-propylamino) propyl, group 4- (di-n-propylamino) butyl, group 5- (di-n-propylamino) pentyl, group 6- (di-n-propylamino) hexyl, group 2- (phenylamino ) ethyl, group

3- (phenylamino) propyl, group 4- (phenylamino) butyl, group 5- (phenylamino) pentyl, group 6-

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235/854 group group

2- (N-methyl-N-phenylamino) ethyl,

4- (N-methyl-N-phenylamino) butyl, group 6- (N-methyl-N-phenylamino) hexyl, group (3,4-dimethoxyphenyl) aminomethyl, group group

3- (N-methyl-N5- (N-methyl-Ngroup (4group (2,4,6 (phenylamino) hexyl, phenylamino) proyila, phenylamino) pentyl, methoxyphenyl) aminomethyl, trimethoxyphenyl) aminomethyl, group 2- (4- trifluoromethoxyphenylamino) ethyl, group 3- (4trifluoromethoxyphenylamino) propyl, group 4- (4-trifluoromethoxyphenylamino) butyl, group 5 (4-trifluoromethoxyphenylamino) pentyl, group 6- (4-trifluoromethoxyphenylamino) hexyl-group 2- (2- -4-trifluoromethoxyphenylamino) ethyl, trifluoromethoxyphenylamino) propyl, trifluoromethoxyphenylamino) butyl, trifluoromethoxyphenylamino) pentyl, trifluoromethoxyphenylamino) hexyl or the like.

[0320] A 1,2,3,6-tetrahydropyridyl C1-6 alkyl group (which can be substituted on the 1,2,3,6-tetrahydropyridine ring by at least one phenyl group that can have at least one C1- alkoxy group 6 unsubstituted or substituted by halogen as a substituent on the phenyl ring) includes a 1,2,3,6-tetrahydropyridyl C1-6 alkyl group (which can be substituted on the 1,2,3,6-tetrahydropyridine ring by 1 to 3 phenyl groups that can have from 1 to 3 C1-6 alkoxy group unsubstituted or substituted by halogen group group group group

3- (N-methyl-N-4-

4- (N-methyl-N-4-

5- (N-methyl-N-4-

6- (N-methyl-N-4- as a substituent on the phenyl ring), for example, methyl group (1,2,3,6-tetrahydropyridin-1-yl) methyl, group 1- (1,2,3,6 -tetrahydropyridin-2-yl) ethyl, group 2- (1,2,3,6-tetrahydropyridin-3yl) ethyl, group 3- (1,2,3,6-tetrahydropyridin-4-yl) propyl, group 4- (1,2,3,6-tetrahydropyridin-lil) butyl, group 5- (1,2,3,6-tetrahydropyridin-2-yl) pentyl, group 6- (1,2,3,6-tetrahydropyridin-3 il) hexyl, 2-methyl-3- (1,2,3,6-tetrahydropyridin-1-yl) propyl group, 1,1-dimethyl-2 (1,2,3,6-tetrahydropyridin-4-yl group ) ethyl, 4-phenyl-1,2,3,6-tetrahydropyridin-1-ylmethyl group, group

3,4,5-triphenyl-1,2,3,6-tetrahydropyridin-1-ylmethyl, group 3,4-diphenyl-1,2,3,6-tetrahydropyridin-

1-ylmethyl, group 4- (2-methoxyphenyl) -1,2,3,6-tetrahydropyridin-1-ylmethyl, group 4- (3-methoxyphenyl) -1,2,3,6-tetrahydropyridin-1-methylmethyl, group 4- (4-methoxyphenyl) -1,2,3,6tetrahydropyrid in-1-ylmethyl, group 4- (2,4-dimethoxyphenyl) -1,2,3,6-tetrahydropyridin-1-ylmethyl, group 3- (2,4,6-trimethoxyphenyl) -1,2,3,6-tetrahydropyridin-1-ylmethyl, group 4- (2trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridin-1-ylmethyl, group 4- (3 -trifluoromethoxyphenyl) Petition 870190039560, of 04/26/2019, p. 244/876

236/854

1,2,3,6-tetrahydropyrid in-1-methylmethyl, group 4- (3,5-ditrifluoromethoxyphenyl) -1,2,3,6-tetrahydropyrid in-1-methylmethyl, group 4- (4-trifluoromethoxyphenyl) - 1,2,3,6-tetrahydropyrid in-1-ylmethyl, group 2- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) ethyl, group 2- [4- (4-methoxyphenyl) -

1.2.3.6- tetrahydropyrid in-1-yl] ethyl, group 2- [4- (4-trifluoromethoxyphenyl) -1,2,3,6tetrahydropyridin-1-yl] ethyl, group 3- (4-pheni 1-1 , 2,3,6-tetrahydropyridin-1-yl) propyl, group 3- [4 (4-methoxyphenyl) -1,2,3,6-tetrahydropyridin-1-yl] propyl, group 3- [4- (4 -trifluoromethoxyphenyl) -

1.2.3.6- tetrahydropyridin-1-yl] propyl, group 4- (4-pheni 1-1,2,3,6-tetrahydropyridin-1 -yl) butyl, group 4- [4- (4-methoxyphenyl) -1 , 2,3,6-tetrahydropyridin-1-yl] butyl, group 4- [4- (4trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyrid in-1 -yl] butyl, group 5- (4-phen yl-1,2,3,6tetrahydropyrid in-1 -yl) pentyl, group 5- [4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyrid in-1 yl] pentyl, group 5- [4 - (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridin-1-yl] pentyl, group 6 (4-phenyl 1-1,2,3,6-tetrahydropyrid in-1-yl) hexyl, group 6- [4- (4-methoxyphenyl) -1,2,3,6tetrahydropyridin-1-yl] hexyl, group 6- [4- (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridin-1 yl] hexyl or similar.

[0321] Examples of a fluorenyl C1-6 alkyl group include a 1fluorenylmethyl group, 2-fluorenylmethyl group, 3-fluorenylmethyl group, 4-fluorenylmethyl group, 9-fluorenylmethyl group, 2- (1-fluorenyl) ethyl group, 2- group (2-fluorenyl) ethyl, group 2- (3-fluorenyl) ethyl, group 2- (4-fluorenyl) ethyl, group 2- (9-fluorenyl) ethyl, group 3- (1-fluorenyl) propyl, group 3- (2-fluorenyl) ) propyl, group 3- (3-fluorenyl) propyl, group 3- (4-fluorenyl) propyl, group 3- (9-fluorenyl) propyl, group 4- (1-fluorenyl) butyl, group 4- (2-fluorenyl) butyl, group 5- (1-fluorenyl) pentyl, group 5- (2-fluorenyl) pentyl, group 6- (1-fluorenyl) hexyl, group 6- (2-fluorenyl) hexyl or the like.

[0322] A C1-6 furyl alkyl group (which can be substituted on the furan ring with an unsubstituted or halogen substituted phenyl group) includes a C1-6 furyl alkyl group (which can be substituted on the furan ring with a non-phenyl group) substituted or substituted by 1 to 5 halogen atoms, for example, a 2-furylmethyl group, 3-furylmethyl group, 2- (2-furyl) ethyl group, 1- (3-furyl) ethyl group, group 3- ( 2-furyl) propyl, group 3- (3-furyl) propyl, group 4- (2-furyl) butyl, group 4- (3-furyl) butyl, group 5- (2-furyl) pentyl, group 5- (3- furyl) pentyl, group 6- (2-furyl) hexyl, group 6- (3-furyl) hexyl, group 4-phenyl-2-furylmethyl, group 4- (2-fluorophenyl) -2-furylmethyl, group 4- ( 3-fluorophenyl) Petition 870190039560, of 26/04/2019, page 245/876

237/854

2-furylmethyl, group 4- (4-fluorophenyl) -2-furylmethyl, group 4- (2,3,4,5,6-pentafluorophenyl) 2-furylmethyl, group 4- (2-chlorophenyl) -2-furylmethyl, group 4- (3-chlorophenyl) -2-furylmethyl, group 4- (4-chlorophenyl) -2-furylmethyl, group 4- (2-bromophenyl) -2-furylmethyl, group 4- (3bromophenyl) -2-furylmethyl, group 4- (4-bromophenyl) -2-furylmethyl, group 4-phenyl-3-furylmethyl, group 4- (2,3-dichlorophenyl) -3-furylmethyl, group 4- (4-chlorophenyl) -3-furylmethyl, group 4 - (2-bromophenyl) -3-furylmethyl, group 4- (3-bromophenyl) -3-furylmethyl, group 4- (4bromophenyl) -3-furylmethyl, group 4-phenyl-3-furylethyl, group 2- [4- (3-chlorophenyl) -3-furyl] ethyl, group 2- [4- (4-chlorophenyl) -3-furyl] ethyl, group 2- [4- (2-bromophenyl) -3-furyl] ethyl, group 2 - [4 (3-bromophenyl) -3-furyl] ethyl, group 2- [4- (2,4-dibromophenyl) -3-furyl] ethyl, group 2- (4-phenyl-2furyl) ethyl, group 2- [4- (3-chlorophenyl) -2-furyl] ethyl, group 2- [4- (4-chlorophenyl) -2-furyl] ethyl, group 2- [4- (4-bromophenyl) -2-furyl] ethyl , group 3- (4-phenyl-3-furyl) propyl, group 3- [4- (3-chlorophenyl ) -3-furyl] propyl, group 3- [4- (2,4,6-trichlorophenyl) -3-furyl] propyl, group 3- [4- (4bromophenyl) -3-furyl] propyl, group 3- ( 4-phenyl-2-furyl) propyl, group 3- [4- (3-chlorophenyl) -2furyl] propyl, group 3- [4- (4-chlorophenyl) -2-furyl] propyl, group 3- [4- (4-bromophenyl) -2furyl] propyl, group 4- (4-phenyl-3-furyl) butyl, group 4- [4- (3-chlorophenyl) -3-furyl] butyl, group

4- [4- (4-chlorophenyl) -3-furyl] butyl, group 4- [4- (4-bromophenyl) -3-furyl] butyl, group 4- (4-phenyl2-furyl) butyl, group 4- [4- (3-chlorophenyl) -2-furyl] butyl, group 4- [4- (4-chlorophenyl) -2furyl] butyl, group 4- [4- (4-bromophenyl) -2-furyl] butyl, group 5- (4-phenyl-3-furyl) pentyl, group

5- [4- (3-chlorophenyl) -3-furyl] pentyl, group 5- [4- (4-chlorophenyl) -3-furyl] pentyl, group 5- [4- (4bromophenyl) -3-furyl] pentyl , group 5- (4-phenyl-2-furyl) pentyl, group 5- [4- (3-chlorophenyl) -2furyl] pentyl, group 5- [4- (4-chlorophenyl) -2-furyl] pentyl, group 5- [4- (4-bromophenyl) -2furyl] pentyl, group 6- (4-phenyl-3-furyl) hexyl, group 6- [4- (3-chlorophenyl) -3-furyl] hexyl, group

6- [4- (4-chlorophenyl) -3-furyl] hexyl, group 6- [4- (4-bromophenyl) -3-furyl] hexyl, group 6- (4-phenyl-2-furyl) hexyl, group 6- [4- (3-chlorophenyl) -2-furyl] hexyl, group 6- [4- (4-chlorophenyl) -2furyl] hexyl, group 6- [4- (4-bromophenyl) -2-furyl] hexyl or similar .

[0323] Examples of a C1-6 alkyl group substituted by thienyl include a 2-thienylmethyl group, 3-thienylmethyl group, 2- (2-thienyl) ethyl group, 1- (3-thienyl) ethyl group, group

4- (2-thienyl) butyl, group 4- (3-thienyl) butyl, group 5- (2-thienyl) pentyl, group 5- (3-thienyl) pentyl, group 6- (2-thienyl) hexyl, group 6- (3-thienyl) hexyl or the like.

[0324] An oxazolyl C1-6 alkyl group (which can be substituted on the oxazole ring by

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238/854 a halogen atom or a phenyl group unsubstituted or substituted by halogen) includes an oxazolyl C1-6 alkyl group (which can be replaced on the oxazole ring by a halogen atom or 1 to 2 phenyl groups which can be substituted in the phenyl ring by 1 to 5 halogen atoms), for example, a 2oxazolylmethyl group, 4-oxazolylmethyl group, 5-oxazolylmethyl group, 2- (2-oxazolyl) ethyl group, group 1 - (4-oxazolyl) ethyl, group 3- (2-oxazolyl) propyl, group 4- (2-oxazolyl) butyl, group

5- (2-oxazolyl) pentyl, group 6- (2-oxazolyl) hexyl, group 2- (4-oxazolyl) ethyl, group 3- (4oxazolyl) propyl, group 4- (4-oxazolyl) butyl, group 5- (4-oxazolyl) pentyl, group 6- (4oxazolyl) hexyl, group 2-chloro-4-oxazolylmethyl, group 2,5-dichloro-4-oxazolylmethyl, group 2,5-diphenyl-4-oxazolylmethyl, group 2- ( 2-chloro-4-oxazolyl) ethyl, group 3- (2-chloro-4oxazolyl) propyl, group 4- (2-iodo-4-oxazolyl) butyl, group 5- (2-bromo-4-oxazolyl) pentyl, group 6- (2-fluoro-4-oxazolyl) hexyl, group 2- (4-chlorophenyl) -4-oxazolylmethyl, group 2 (2,3,4,5,6-pentafluorophenyl) -4-oxazolylmethyl, group 2- [2- (4-chlorophenyl) -4-oxazolyl] ethyl, group 3- [2- (4-chlorophenyl) -4-oxazolyl] propyl, group 4- [2- (2,4,6-trichlorophenyl) -4oxazolyl ] butyl, group 5- [2- (4-chlorophenyl) -4-oxazolyl] pentyl, group 6- [2- (4-chlorophenyl) -4oxazolyl] hexyl, group [2-chloro-4- (3-chlorophenyl) -5-oxazolyl] methyl or the like.

[0325] An oxadiazolyl C1-6 alkyl group (which can be substituted on the oxadiazole ring by an unsubstituted or halogen substituted phenyl group) includes an oxadiazolyl C1-6 alkyl group (which can be substituted on the oxadiazol ring by a non-phenyl group substituted or substituted by 1 to 5 halogen atoms), for example, a 5-oxadiazolylmethyl group, 2- (5-oxadiazolyl) ethyl group, group 1 - (2-oxadiazolyl) ethyl, group 3- (5-oxadiazolyl) propyl, 4- (2-oxadiazolyl) butyl group, 5- (5oxadiazolyl) pentyl group, 6- (2-oxadiazolyl) hexyl group, 2-methyl-3- (2oxadiazolyl) propyl group, 1,1-dimethyl-2 group - (5-oxadiazolyl) ethyl, group 2-phenyl-5oxadiazolylmethyl, group 2- (2-fluorophenyl) -5-oxadiazolylmethyl, group 2- (3-fluorophenyl) -5oxadiazolylmethyl, group 2- (2,3,4,5 , 6-pentafluorophenyl) -5-oxadiazolylmethyl, group 2 (2,4-dichlorophenyl) -5-oxadiazolylmethyl, group 2- (3-chlorophenyl) -5-oxadiazolylmethyl, group 2- (4-chlorophenyl) -5-oxadiazolylmethyl, group 2- (2-bromophenyl) -5-oxadiazolylmethyl a, group 2- (2,4,6-tribromophenyl) -5-oxadiazolylmethyl, group 2- (4-bromophenyl) -5-oxadiazolylmethyl, group 2- (5-oxadiazolyl) ethyl, group 3- (5-oxadiazolyl) propyl, group 4- (5

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239/854 oxadiazolyl) butyl, group 5- (5-oxadiazolyl) pentyl, group 6- (5-oxadiazolyl) hexyl, group

2- (2-phenyl-5-oxadiazolyl) ethyl, group 3- (2-phenyl-5-oxadiazolyl) propyl, group 4- (2-phenyl-5oxadiazolyl) butyl, group 5- (2-phenyl-5-oxadiazolyl ) pentyl, group 6- (2-phenyl-5oxadiazolyl) hexyl, group 2- [2- (4-chlorophenyl) -5-oxadiazolyl] ethyl, group 3- [2- (4-chlorophenyl) -

5-oxadiazolyl] propyl, group 4- [2- (4-chlorophenyl) -5-oxadiazolyl] butyl, group 5- [2- (4-chlorophenyl) -5-oxadiazolyl] pentyl, group 6- [2- (4-chlorophenyl ) -5-oxadiazolyl] hexyl or the like.

[0326] A C 1-6 pyrazolyl alkyl group (which can be substituted on the pyrazole ring by an unsubstituted or halogen substituted phenyl group) includes a C 1-6 pyrazolyl alkyl group (which can be substituted on the pyrazole ring by 1 to 3 phenyl groups not substituted or substituted by 1 to 5 halogen atoms), for example, a group

3- pyrazolylmethyl, group 2- (4-pyrazolyl) ethyl, group 1 - (5-pyrazolyl) ethyl, group 3- (3-pyrazolyl) propyl, group 4- (4-pyrazolyl) butyl, group 5- (1-pyrazolyl) pentyl, group 6- (5pyrazolyl) hexyl, group 2-methyl-3- (1-pyrazolyl) propyl, group 1,1-dimethyl-2- (3pyrazolyl) ethyl, group 1 - (1-phenyl-3-pyrazolylmethyl, group 1 - (2-fluorophenyl) -4-pyrazolylmethyl, group 1 - (3-fluorophenyl) -3-pyrazolylmethyl, group 3-phenyl-1-pyrazolylmethyl, group 3,4,5 triphenyl-1-pyrazolylmethyl, group 3,4 -diphenyl-1-pyrazolylmethyl, group 1- (4-fluorophenyl) -3 pyrazolylmethyl, group 1- (2,3,4,5,6-pentafluorophenyl) -3-pyrazolylmethyl, group 1- (2chlorophenyl) -5-pyrazolylmethyl, group 1 - (3-chlorophenyl) -3-pyrazolylmethyl, group 1- (4-chlorophenyl) -3-pyrazolylmethyl, group 1- (2-bromophenyl) -3-pyrazolylmethyl, group 1- (3bromophenyl) -3-pyrazolylmethyl, group 1 - (4-bromophenyl) -3-pyrazolylmethyl, group 2- (3-pyrazolyl) ethyl, group 3- (3-pyrazolyl) propyl, group 4- (3-pyrazolyl) butyl, group 5- (3pyrazolyl) pentyl, group 6- (3-pyrazolyl) hexyl , group 2- [1 - (4-chlorophenyl) -3-pyrazolyl] ethyl, group 3- [1 - (2,4-dichlorophenyl) -3-pyrazolyl] propyl, group 4- [1- (4-chlorophenyl) -3pyrazolyl] butyl, group 5- [1 - (4-chlorophenyl) -3-pyrazolyl] pentyl, group 6- [1 - (2,4,6trichlorophenyl) -3-pyrazolyl] hexyl or the like.

[0327] A benzothienyl C1-6 alkyl group (which may be substituted on the benzothiophene ring by at least one group selected from a group consisting of a halogen atom and an unsubstituted or substituted halogen C1-6 alkoxy group) includes a benzothienyl C1-6 alkyl group (which can be substituted on the ring

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240/854 benzothiophene by 1 to 3 groups selected from a group of a halogen atom and a C1-6 alkoxy group unsubstituted or substituted by halogen), for example, a 2-benzothienylmethyl group, group group 3- (5- benzothienyl) propyl, benzothienyl) pentyl, benzothienyl) propyl, benzothienylmethyl, benzothienylmethyl, benzothienylmethyl, group 5-chloro-2-benzothienylmethyl, group 6-chloro-2-benzothienylmethyl, group 7-chloro-2-benzothienylmethyl, group 4-bromo-methyl 2-benzothienylmethyl, 5-bromo group group group group group

2- (3-benzothienyl) ethyl, group 1- (4-benzothienyl) ethyl, group 4- (6-benzothienyl) butyl, group 5- (76- (2-benzothienyl) hexyl, group

1,1-dimethyl-2- (2-benzothienyl) ethyl,

5-fluoro-2-benzothienylmethyl,

7-fluoro-2-benzothienylmethyl, group group group

2-methyl-3- (34-fluoro-26-fluoro-24-chloro-22-benzothienylmethyl, group 6-bromo-2-benzothienylmethyl, group 7-bromo-2benzothienylmethyl, group 4-methoxy-2-benzothienylmethyl, group 5 -methoxy-2benzothienylmethyl, 6-methoxy-2-benzothienylmethyl group, 6,7-dimethoxy-2benzothienylmethyl group, 3,6,7-trimethoxy-2-benzothienylmethyl group, 7-methoxy-2benzothienylmethyl group, 4-trifluoromethoxy-2- group benzothienylmethyl, 5-trifluoromethoxy2-benzothienylmethyl group, 6-trifluoromethoxy-2-benzothienylmethyl group, 7trifluoromethoxy-2-benzothienylmethyl group, 4-ethoxy-2-benzothienylmethyl group, 5-ethoxy-2-benzothienylmethyl group, group 5-ethoxy-2-benzothienylmethyl 7-ethoxy-2-benzothienylmethyl group, 4-chloro-5-trifluoromethoxy-2-benzothienylmethyl group, 6-chloro-5-trifluoromethoxy-2benzothienylmethyl group, 7-chloro-5-trifluoromethoxy-2-benzothienylmethyl group, 3benzotien group 4-fluoro-3-benzothienylmethyl, group 5-fluoro-3benzothienylmethyl, group 6-fluoro-3-benzothienylmethyl, group 7-fluoro-3benz otienylmethyl, 4-chloro-3-benzothienylmethyl group, 5-chloro-3-benzothienylmethyl group, 6-chloro-3-benzothienylmethyl group, 7-chloro-3-benzothienylmethyl group, 4-bromo-3 group group group

5-bromo-3-benzothienylmethyl,

7-bromo-3-benzothienylmethyl,

5-methoxy-3-benzothienylmethyl, group group group

6-bromo-34-methoxy-36-methoxy-3group 7-methoxy-3-benzothienylmethyl group, 4-trifluoromethoxy-3benzothienylmethyl, benzothienylmethyl, benzothienylmethyl, benzothienylmethyl, benzothienylmethyl, 5-trifluoromethoxy-3-trifluoromethoxy group

3-benzothienylmethyl, group 7-trifluoromethoxy-3-benzothienylmethyl, group 4-ethoxy-3Petition 870190039560, of 26/04/2019, p. 249/876

241/854 benzothienylmethyl, 5-ethoxy-3-benzothienylmethyl group, 6-ethoxy-3-benzothienylmethyl group, 7-ethoxy-3-benzothienylmethyl group, 4-chloro-5-trifluoromethoxy-3-benzothienylmethyl group, 6-chloro-methyl group 5-trifluoromethoxy-3-benzothienylmethyl, group 7-chloro-5-trifluoromethoxy-3benzothienylmethyl, group 2- (2-benzothienyl) ethyl, group 3- (2-benzothienyl) propyl, group 4 (2-benzothienyl) butyl, group 5 - (2-benzothienyl) pentyl, group 6- (2-benzothienyl) hexyl, group 2- (3-benzothienyl) ethyl, group 3- (3-benzothienyl) propyl, group 4- (3 group group group

5- (5-chloro-2-benzothienyl) pentyl,

2- (5-chloro-3-benzothienyl) ethyl,

4- (5-chloro-3-benzothienyl) butyl, group group group

6- (5-chloro-23- (5-chloro-35- (5-chloro-3benzothienyl) butyl, group 5- (3-benzothienyl) pentyl, group 6- (3-benzothienyl) hexyl, group 2- (5 -chloro-2-benzothienyl) ethyl, group 3- (5-chloro-2-benzothienyl) propyl, group 4- (5-chloro2-benzothienyl) butyl, benzothienyl) hexyl, benzothienyl) propyl, benzothienyl) pentyl, group 6- (5-chloro-3-benzothienyl) hexyl or the like.

[0328] A C1-6 thienyl alkyl group that can be substituted on the thiophene ring with a halogen atom includes a C1-6 thienyl alkyl group (which can be replaced on the thiophene ring with 1 to 3 halogen atoms, for example, a 2-thienylmethyl group, 2- (3-thienyl) ethyl group, 1- (2-thienyl) ethyl group, 3- (2-thienyl) propyl group, 4- (3-thienyl) butyl group, group 5- ( 2-thienyl) pentyl, group 6- (2-thienyl) hexyl, group 2-methyl-3- (3-thienyl) propyl, group 1,1-dimethyl-2- (2-thienyl) ethyl, group 3-fluoro -2-thienylmethyl, 4-fluoro-2-thienylmethyl group, 3,4-difluoro-2-thienylmethyl group, 3,4,5-trichloro-2-thienylmethyl group, 5-fluoro-2 thienylmethyl group, 3-chloro-group 2-thienylmethyl, 4-chloro-2-thienylmethyl group, 5-chloro-2-thienylmethyl group, 3-bromo-2-thienylmethyl group, 4-bromo-2-thienylmethyl group, 5bromo-2-thienylmethyl group, 3-thienylmethyl group, 2-fluoro-3-thienylmethyl group, 4-fluoro group

3-thienylmethyl, 5-fluoro-3-thienylmethyl group, 2-chloro-3-thienylmethyl group, 4-chloro3-thienylmethyl group, 5-chloro-3-thienylmethyl group, 2-bromo-3-thienylmethyl group, 4bromo- group 3-thienylmethyl, group 5-iodo-3-thienylmethyl, group 2- (5-chloro-2-thienyl) ethyl, group 3- (5-chloro-2-thienyl) propyl, group 4- (5-chloro-2 -thienyl) butyl, group 5- (5-chloro-2-thienyl) pentyl, group 6- (5-chloro-2-thienyl) hexyl, group 2- (5-chloro-3-thienyl) ethyl, group 3- ( 5chloro-3-thienyl) propyl, group 4- (5-chloro-3-thienyl) butyl, group 5- (5-chloro-3-thienyl) pentyl, group 6- (5-chloro-3-thienyl) hexyl or similar.

[0329] Examples of a benzothiazolyl C1-6 alkyl group include a group

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242/854 benzothiazol-2-ylmethyl, benzothiazol-4-ylmethyl group, benzothiazol-5-ylmethyl group, benzothiazol-6-ylmethyl group, benzothiazol-7-ylmethyl group, ethyl group 2- (benzothiazol-4-yl) ethyl, group 2- (benzothiazol-5-yl) methyl, group 2- (benzothiazol-6-yl) ethyl, group 2- (benzothiazol-7yl) ethyl, group 3- (benzothiazol-4-yl) propyl, group 3- (benzothiazol-5 -yl) propyl, group 3 (benzothiazol-6-yl) propyl, group 3- (benzothiazol-7-yl) propyl, group 4- (benzothiazol-2yl) butyl, group 4- (benzothiazol-4-yl) butyl, group 4- (benzothiazol-5-yl) butyl, group 4 (benzothiazol-6-yl) butyl, group 4- (benzothiazol-7-yl) butyl, group 5- (benzothiazol-2yl) pentyl, group 5- (benzothiazole -4-yl) pentyl, group 5- (benzothiazol-5-yl) pentyl, group 5 (benzothiazol-6-yl) pentyl, group 5- (benzothiazol-7-yl) pentyl, group 6- (benzothiazol-2il) hexyl, group 6- (benzothiazol-4-yl) hexyl, group 6- (benzothiazol-5-yl) hexyl, group 6 (benzothiazol-6-yl) hexyl, group 6- (benzothiazol-7-yl) hexyl or similar .

[0330] A benzofuryl C1-6 alkyl group that can be substituted on the benzofuran ring by a halogen atom as a substituent includes a benzofuryl C1-6 alkyl group that can be substituted on the benzofuran ring by 1 to 3 halogen atoms as a substituent, for example, a 2-benzofurylmethyl group, 2- (3-benzofuryl) ethyl group, 1- (4-benzofuryl) ethyl group, 3- (5-benzofuryl) propyl group, 4- (6-benzofuryl) butyl group , 5- (7-benzofuryl) pentyl group, 6- (2benzofuryl) hexyl group, 2-methyl-3- (3-benzofuryl) propyl group, 1,1-dimethyl-2- (2benzofuryl) ethyl group, group 4- fluoro-2-benzofurylmethyl, group 5-fluoro-2-benzofurylmethyl, group 6-fluoro-2-benzofurylmethyl, group 7-fluoro-2-benzofurylmethyl, group 4-chloro-2benzofurylmethyl, group 5-chloro-2-benzofurylmethyl, group 6-chloro-2-benzofurylmethyl, 7-chloro-2-benzofurylmethyl group, 4-bromo-2-benzofurylmethyl group, 5-bromo-2benzofurylmethyl group, 6-bromo-2-benzofurylmethyl group, 7-bromo-2-benzofurylmethyl group , 4-iodine group -2-benzofurylmethyl, 5-iodo-2-benzofurylmethyl group, 6-iodo-2-benzofurylmethyl group, 7-iodo-2-benzofurylmethyl group, 4-fluoro-3-benzofurylmethyl group, 5-fluoro-3-benzofurylmethyl group, group 5 , 6-difluoro-2-benzofurylmethyl, 7fluoro-3-benzofurylmethyl group, 4-chloro-3-benzofurylmethyl group, 3,5,6-trichloro-3-benzofurylmethyl group, 6-chloro-3-benzofurylmethyl group, 7-chloro-group 3-benzofurylmethyl, 4-bromo-3-benzofurylmethyl group, 5-bromo-3-benzofurylmethyl group, 6-bromo3-benzofurylmethyl group, 7-bromo-3-benzofurylmethyl group, 4-iodo-3-benzofurylmethyl group,

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243/854 5-iodo-3-benzofurylmethyl group, 6-iodo-3-benzofurylmethyl group, 7-iodo-3benzofuryl methyl group or the like.

[0331] A C1-6 alkyl indolinyl group (which can be substituted on the indoline ring by at least one group selected from a group consisting of a C1-6 alkyl group and an oxo group) includes a C1-6 alkyl indolinyl group ( which can be substituted on the indoline ring by 1 to 5 groups selected from a group consisting of a C1-6 alkyl group and an oxo group), for example, a 2-indolinylmethyl group, 2- (3indolinyl) ethyl group, 1- (4-indolinyl) ethyl, group 3- (5-indolinyl) propyl, group 4- (6-indolinyl) butyl, group 5- (7-indolinyl) pentyl, group 6- (1-indolinyl) hexyl, group 2- methyl-3 (3-indolinyl) propyl, group 1,1-dimethyl-2- (2-indolinyl) ethyl, group 3,3-dimethyl-5indolinylmethyl, group 1,3,3-trimethyl-5-indolinylmethyl, group 1 -ethyl-3,3-dimethyl-5indolinylmethyl, group 1 -methyl-5-indolinimethyl, group 1,3-dimethyl-5-indolinylmethyl, group 1,3,3,6,7-pentamethyl-5-indoliniImethyl, group 3 , 3-dimethyl-1 - (n-propyl) -5-indoliniImethyl, group 3,3-dimethyl-1- (isopropyl) -5-indolinylmethyl, gr upo 1- (n-butyl) -3,3-dimethyl-5indolinylmethyl, group 1 - (sec-butyl) -3,3-dimethyl-5-indolinylmethyl, group 1- (ter-butyl) -3,3dimethyl-5 -indolinylmethyl, group 1- (n-pentyl) -3,3-dimethyl-5-indolinylmethyl, group 1- (nhexyl) -3,3-dimethyl-5-indolinylmethyl, group 3,3-dimethyl-2-oxo- 5-indolinylmethyl, group

1.3.3- trim ethyl-2-oxo-5-indolinylmethyl, group 1-ethyl-3,3-dimethyl-2-oxo-5-indolinylmethyl, group 3,3-dimethyl-2-oxo-1 - ( n-propyl) -5-indolinylmethyl, group 3,3-dimethyl-2-oxo-1 (isopropyl) -5-indolinylmethyl, group 1 - (n-butyl) -3,3-dimethyl-2-oxo-5- indolinylmethyl, group 1 - (sec-butyl) -3,3-dimethyl-2-oxo-5-indolinylmethyl, group 1 - (ter-butyl) -3,3-dimethyl-2-oxo-5indolinylmethyl, group 1 - ( n-pentyl) -3,3-dimethyl-2-oxo-5-indolinylmethyl, group l- (n-hexyl) -

3.3- dimethyl-2-oxo-5-indolinylmethyl, 2-oxo-5-indolinyl methyl group or the like.

[0332] A benzoxazolyl C1-6 alkyl group (which can be substituted on the benzoxazole ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group and oxo group) includes C1-6 alkyl benzoxazyl group 6 (which can be substituted on the benzoxazole ring by 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group and oxo group), for example, a benzoxazol-2-ylmethyl group, benzoxazole group -4-ylmethyl, benzoxazol-5-ylmethyl group, benzoxazol-6-ylmethyl group, benzoxazol-7-ylmethyl group, 2Petition 870190039560, from 26/04/2019, p. 252/876

244/854 (benzoxazol-2-yl) ethyl, group 1- (benzoxazol-4-yl) ethyl, group 3- (benzoxazol-5-yl) propyl, group 4- (benzoxazol-6-yl) butyl, group 5 - (benzoxazol-7-yl) pentyl, group 6- (benzoxazol2-yl) hexyl, group 2-methyl-3- (benzoxazol-4-yl) propyl, group 1,1-dimethyl-2- (benzoxazol-

5-yl) ethyl, 2,5-dimethylbenzoxazol-4-ylmethyl group, 2,5,6-trimethylbenzoxazol-4ylmethyl group, 4,5-dichlorobenzoxazol-4-ylmethyl group, 2,4,5-trichlorobenzoxazol-4ylmethyl group, (2,3-dihydro-2-oxo-benzoxazol-3-yl) methyl group, (2,3-dihydro-2-oxobenzoxazol-4-yl) methyl group, (2,3-dihydro-2-oxo- benzoxazol-5-yl) methyl, (2,3-dihydro-2-oxo-benzoxazol-6-yl) methyl, group (2,3-dihydro-2-oxo-benzoxazol-7-yl) methyl, group 2- ( benzoxazol-4-yl) ethyl, (benzoxazol-5-yl) methyl, group 2- (benzoxazol-6-yl) ethyl, group 2- (benzoxazol-7-yl) ethyl, group 2- (2,3-dihydro -2-oxo-benzoxazol-3-yl) ethyl, group 2 (2,3-dihydro-2-oxo-benzoxazol-4-yl) ethyl, group 2- (2,3-dihydro-2-oxo-benzoxazole- 5-yl) ethyl, group 2- (2,3-dihydro-2-oxo-benzoxazol-6-yl) ethyl, group 2- (2,3-dihydro-2-oxo-benzoxazol-

7-yl) ethyl, group 3- (benzoxazol-2-yl) propyl, group 3- (benzoxazol-4-yl) propyl, group 3 (benzoxazol-6-yl) propyl, 3- (benzoxazol-7-yl) propyl, group 3- (2,3-dihydro-2-oxobenzoxazol-3-yl) propyl, group 3- (2,3-dihydro-2-oxo-benzoxazol-4-yl) propyl, group 3 (2,3 -dihydro-2-oxo-benzoxazol-5-yl) propyl, group 3- (2,3-dihydro-2-oxo-benzoxazol-6yl) propyl, group 3- (2,3-dihydro-2-oxo-benzoxazole -7-yl) propyl, group 4- (benzoxazol-2yl) butyl, group 4- (benzoxazol-4-yl) butyl, group 4- (benzoxazol-5-yl) butyl, group 4 (benzoxazol-7-yl) butyl, 4- (2,3-dihydro-2-oxo-benzoxazol-3-yl) butyl, group 4- (2,3-dihydro2-oxo-benzoxazol-4-yl) butyl, group 4- (2,3 -dihydro-2-oxo-benzoxazol-5-yl) butyl, group 4 (2,3-dihydro-2-oxo-benzoxazol-6-yl) butyl, group 4- (2,3-dihydro-2-oxo- benzoxazol-7yl) butyl, group 5- (benzoxazol-2-yl) pentyl, 5- (benzoxazol-4-yl) pentyl, group 5 (benzoxazol-5-yl) pentyl, group 5- (benzoxazol-6-yl) pentyl, group 5- (2,3-dihydro-2-oxobenzoxazol-3-yl) pentyl, group 5- (2,3-dihydro-2-oxo-benzoxazol-4-yl) pentyl, group 5 (2,3-dihydro-2-oxo-benzoxazol-5-yl) pentyl, group 5- (2,3-dihydro-2-oxo-benzoxazol-6yl) pentyl, group 5- (2,3-dihydro- 2-oxo-benzoxazol-7-yl) pentyl, group 6- (benzoxazol-4yl) hexyl, 6- (benzoxazol-5-yl) hexyl, group 6- (benzoxazol-6-yl) hexyl, group 6 (benzoxazol- 7-yl) hexyl, group 6- (2,3-dihydro-2-oxo-benzoxazol-3-yl) hexyl, group 6- (2,3-dihydro-2-oxo-benzoxazol-4-yl) hexyl, group 6 - (2,3-dihydro-2-oxo-benzoxazol-5-yl) hexyl, group 6- (2,3-dihydro-2-oxo-benzoxazol-6-yl) hexyl, group 6- (2,3- dihydro-2-oxo-

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245/854 benzoxazol-7-yl) hexyl, 2-methylbenzoxazol-4-ylmethyl group, 2-methylbenzoxazole- group

5-ylmethyl, 2-methylbenzoxazol-6-ylmethyl group, 4-methylbenzoxazol-2-ylmethyl group, 5-methylbenzoxazol-2-ylmethyl group, 6-methylbenzoxazol-2-ylmethyl group, 7methylbenzoxazol-2-ylmethyl group, group 2- ethylbenzoxazol-4-ylmethyl, group 2-ethylbenzoxazol5-ylmethyl, group 2-ethylbenzoxazol-6-ylmethyl, group 2-n-propylbenzoxazol-4-ylmethyl, group 2-n-propylbenzoxazol-5-ylmethyl, group 2-n-propylbenzoxazol -6-ylmethyl, 4fluorobenzoxazol-2-ylmethyl group, 5-fluoro-2-benzoxazolylmethyl group, 6-fluoro-2benzoxazolylmethyl group, 7-fluorobenzoxazol-2-ylmethyl group, 4-chlorobenzoxazol-2ylmethyl group, 5-chloro-2-methyl group -benzoxazol-2-ylmethyl, group 6-chloro-2-benzoxazol-2-ylmethyl, group 7-chloro-2-benzoxazol-2-ylmethyl, group 4-bromo-2-benzoxazol-2-ylmethyl, group 5-bromo -2-benzoxazol-2-ylmethyl, group 6-bromo-2-benzoxazol-2-ylmethyl, group 7bromo-2-benzoxazol-2-ylmethyl, group 4-fluoro-2-oxo-2,3-dihydrobenzoxazol-3- ilmethyl, 5-fluoro-2-oxo-2,3-dihydrobenzoxazol-3-ylmethyl group, 6-fluoro-2-oxo-2,3-d group iidrobenzoxazol-3-ylmethyl, group 7-fluoro-2-oxo-2,3-dihydrobenzoxazol-3-ylmethyl, group 4-chloro-2-oxo-2,3-dihydrobenzoxazol-3-ylmethyl, group 5-chloro-2 -oxo-2,3dihydrobenzoxazol-3-ylmethyl, 6-chloro-2-oxo-2,3-dihydrobenzoxazol-3-ylmethyl group, 7-chloro-2-oxo-2,3-dihydrobenzoxazol-3-ylmethyl group 4-bromo-2-oxo-2,3dihydrobenzoxazol-3-ylmethyl, 5-bromo-2-oxo-2,3-dihydrobenzoxazol-3-ylmethyl group, 6-bromo-2-oxo-2,3-dihydrobenzoxazole- group 3-ylmethyl, 7-bromo-2-oxo-2,3-dihydrobenzoxazol-3-ylmethyl group, 4-fluoro-2-oxo-2,3-dihydrobenzoxazol-5-ylmethyl group, 5-fluoro-2-oxo-2 group , 3-dihydrobenzoxazol-5-ylmethyl, 6-fluoro-2-oxo-2,3-dihydrobenzoxazol-5-ylmethyl group, 7-fluoro-2-oxo-2,3-dihydrobenzoxazol-5-ylmethyl group, 4-chloro-group 2-oxo-2,3-dihydrobenzoxazol-5-ylmethyl, 5-chloro-2-oxo-2,3dihydrobenzoxazol-5-ylmethyl group, 6-chloro-2-oxo-2,3-dihydrobenzoxazol-5-ylmethyl group, 7-chloro-2-oxo-2,3-dihydrobenzoxazol-5-ylmethyl group, 4-bromo-2-oxo-2,3dihydrobenzoxazol-5-ylmethyl group, 5-bromo-2-oxo group -2,3-dihydrobenzoxazol-5-ylmethyl, group 6-bromo-2-oxo-2,3-dihydrobenzoxazol-5-ylmethyl, group 7-bromo-2-oxo-2,3dihydrobenzoxazol-5-ylmethyl, group 4- fluoro-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl, group 5-fluoro-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl, group 6-fluoro-2-oxo-2,3dihydrobenzoxazole-6- ilmethyl, 7-fluoro-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl group,

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246/854 4-chloro-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl group, 5-chloro-2-oxo-2,3dihydrobenzoxazol-6-ylmethyl group, 6-chloro-2-oxo-2 group, 3-dihydrobenzoxazol-6-ylmethyl, group 7-chloro-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl, group 4-bromo-2-oxo-2,3dihydrobenzoxazol-6-ylmethyl, group 5-bromo-2 -oxo-2,3-dihydrobenzoxazol-6-ylmethyl, 6-bromo-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl group, 7-bromo-2-oxo-2,3dihydrobenzoxazol-6-yl methyl group or similar.

[0333] Examples of a C1-6 chromenyl alkyl group include 2-chromenylmethyl group, 3-chromenylmethyl group, 4-chromenylmethyl group, 5-chromenylmethyl group, 6-chromenylmethyl group, 7-chromenylmethyl group, 8-chromenylmethyl group, 2- (2-chromenyl) group ethyl, group 1- (3-chromenyl) ethyl, group 3- (4-chromenyl) propyl, group 4- (5-chromenyl) butyl, group 5- (6-chromenyl) pentyl, group 6- (7-chromenyl) hexyl, group 2 -methyl-3- (8-chromenyl) propyl, 1,1-dimethyl-2- (6chromenyl) ethyl group or the like.

[0334] Examples of a 1,2,3,4-tetrahydroquinolyl C1-6 alkyl group (which can be substituted on the quinoline ring by at least one group selected from a group consisting of a C1-6 alkyl group and an oxo group ) includes a 1,2,3,4tetrahydroquinolyl C1-6 alkyl group (which can be substituted on the quinoline ring by 1 to 3 groups selected from a group consisting of a C1-6 alkyl group and an oxo group), for example , a methyl group (1,2,3,4-tetrahydro-6-quinolyl), group 2- (1,2,3,4tetrahydro-2-quinolyl) ethyl, group 1- (1,2,3,4- tetrahydro-1-quinolyl) ethyl, group 3- (1,2,3,4tetrahydro-3-quinolyl) propyl, group 4- (1,2,3,4-tetrahydro-4-quinolyl) butyl, group 5 (1 , 2,3,4-tetrahydro-5-quinolyl) pentyl, group 6- (1,2,3,4-tetrahydro-6-quinolyl) hexyl, group

2-methyl-3- (1,2,3,4-tetrahydro-7-quinolyl) propyl, 1,1-dimethyl-2- (1,2,3,4-tetrahydro-8quinolyl) ethyl group, group 2- oxo-1,2,3,4-tetrahydro-6-quinolylmethyl, 4-methyl-1,2,3,4tetrahydro-6-quinolylmethyl group, 4-oxo-1,2,3,4-tetrahydro-6- group quinolylmethyl, group 4,6dim eti 1-1,2,3,4-tetrahydro-5-quinoli imethyl, group 1,4,8-trim eti 1-1,2,3,4-tetrahydro-6 quinolylmethyl, group 1-methyl-2-oxo-1,2,3,4-tetrahydro-6-quinolylmethyl, group 1-ethyl-2oxo-1,2,3,4-tetrahydro-6-quinoli Imethyl, group 2-oxo- 1 - (n-propyl) -1,2,3,4-tetrahydro-6quinolylmethyl, group 2-oxo-1- (isopropyl) -1,2,3,4-tetrahydro-6-quinolylmethyl, group 1- ( nbutyl) -2-oxo-1,2,3,4-tetrahydro-6-quinoli Imethyl, group 1 - (sec-butyl) -2-oxo-1,2,3,4

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247/854 tetrahydro-6-quinolyl ethyl, group 1 - (tert-butyl) -2-oxo-1,2,3,4-tetrahydro-6-quinol imethyl, group 1- (n-pentyl) - 2-oxo-1,2,3,4-tetrahydro-6-quinolylmethyl, group 1- (n-hexyl) -2-oxo-

1.2.3.4- tetrahydro-6-quinolylmethyl, group 2- (2-oxo-1,2,3,4-tetrahydro-6-quinolyl) ethyl, group 3- (2-oxo-1,2,3,4- tetrahydro-6-quinolyl) propyl, group 4- (2-oxo-1,2,3,4-tetrahydro-6quinolyl) butyl, group 5- (2-oxo-1,2,3,4-tetrahydro-6- quinolyl) pentyl, group 6- (2-oxo-

1.2.3.4- tetrahydro-6-quinolyl) hexyl, group 2- (1-methyl-2-oxo-1,2,3,4-tetrahydro-6quinolyl) ethyl, group 3- (1-methyl-2- oxo-1,2,3,4-tetrahydro-6-quinolyl) propyl, group 4- (1methyl-2-oxo-1,2,3,4-tetrahydro-6-quinolyl) butyl, group 5- (1 - methyl-2-oxo-1,2,3,4-tetrahydro-

6-quinolyl) pentyl, group 6- (1-methyl-2-oxo-1,2,3,4-tetrahydro-6-quinolyl) hexyl or the like.

[0335] A thiazolyl C1-6 alkyl group (which can be substituted on the thiazole ring by at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted phenyl group by halogen and a C1-6 alkyl group e) includes a thiazolyl C1-6 alkyl group (which can be substituted on the thiazole ring by 1 to 2 groups selected from a group consisting of a halogen atom, unsubstituted phenyl group or substituted by 1 to 5 halogens and a C1-6 alkyl group), for example, a 2-thiazolylmethyl group, 4-thiazolylmethyl group, 5-thiazolylmethyl group, 2- (2-thiazolyl) ethyl group, 1- (4-thiazolyl) ethyl group, group 3- ( 5 thiazolyl) propyl, group 4- (2-thiazolyl) butyl, group 5- (4-thiazolyl) pentyl, group 6- (5 thiazolyl) hexyl, group 2-methyl-3- (2-thiazolyl) propyl, group 1.1 -dimethyl-2- (4-thiazolyl) ethyl, 2-chloro-4-thiazolylmethyl group, 2,5-dichloro-4-thiazolylmethyl group, 2-chloro-5-thiazolylmethyl group, 2-chloro-6-thiazolylmethyl group, group 6 -chlorine-2 -thiazolylmethyl, 5chloro-2-thiazolylmethyl group, 4-chloro-2-thiazolylmethyl group, 5-chloro-4-thiazolylmethyl group, 4-chloro-5-thiazolylmethyl group, 2-ethyl-4-thiazolylmethyl group, group 2,5 -dimethyl-4thiazolylmethyl, 2-methyl-4-thiazolylmethyl group, 2-methyl-5-thiazolylmethyl group, 2methyl-6-thiazolylmethyl group, 6-methyl-2-thiazolylmethyl group, 5-methyl-2-thiazolylmethyl group, group 4 -methyl-2-thiazolylmethyl, 5-methyl-4-thiazolylmethyl group, 4-methyl-5-thiazolylmethyl group, 2-ethyl-4-thiazolylmethyl group, 2-ethyl-5-thiazolylmethyl group, 2-ethyl-6- group thiazolylmethyl, 6-ethyl-2-thiazolylmethyl group, 5-ethyl-2-thiazolylmethyl group, 4-ethyl-2-thiazolylmethyl group, 5-ethyl-4-thiazolylmethyl group, 4-ethyl-5-thiazolylmethyl group, group 2- phenyl-4-thiazolylmethyl,

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248/854 2-phenyl-5-thiazolylmethyl group, 2-phenyl-6-thiazolylmethyl group, 6-phenyl-2-thiazolylmethyl group, 5-phenyl-2-thiazolylmethyl group, 4-phenyl-2-thiazolylmethyl group, group 5 -phenyl-4-thiazolylmethyl,

group 4-phenyl-5-thiazolylmethyl, group 5- (2-fluorophenyl) -2-thiazolylmethyl, group 5- (2,4- difluorophenyl) -4-thiazolylmethyl, group 4- (2-fluorophenyl) -5-thiazolylmethyl, group 2- (2- fluorophenyl) -4-thiazolylmethyl, group 2- (2-fluorophenyl) -5-thiazolylmethyl, group 2- (3- fluorophenyl) -4-thiazolylmethyl, group 2- (3-fluorophenyl) -5-thiazolylmethyl, group 2- (4- fluorophenyl) -4-thiazolylmethyl, group 4- (2-fluorophenyl) -5-thiazolylmethyl, group 2- (2- chlororophenyl) -4-thiazolylmethyl, group 2- (2-chlororophenyl) -5-thiazolylmethyl, group 2- (3- chlororophenyl) -4-thiazolylmethyl, group 2- (2-fluorophenyl) -5-thiazolylmethyl, group 2- (4-

chlororophenyl) -4-thiazolylmethyl, group 2- (4-chlororophenyl) -5-thiazolyl methyl or the like. [0336] A tetrazolyl C1-6 alkyl group (which can be substituted on the tetrazole ring by a group selected from a group consisting of an unsubstituted or halogen-substituted phenyl group and a C1-1 alkyl group) includes a tetrazolyl alkyl group C1-6 (which can be substituted on the tetrazole ring by a group selected from a group consisting of an unsubstituted phenyl group or substituted by 1 to 5 halogen atoms and a C1-8 alkyl group), for example, a group 5- (1 H) -tetrazolylmethyl, group 2- (5- (1 H) -tetrazolyl) ethyl, group 1- (5- (1 H) tetrazolyl) ethyl, group 3- (5- (1 H) -tetrazolyl ) propyl, group 4- (5- (1 (H) -tetrazolyl) butyl, group

5- (5- (1 H) -tetrazolyl) pentyl, group 6- (5- (1 H) -tetrazolyl) hexyl, group 2-methyl-3- (5- (1 H) tetrazolyl) propyl, group 1, 1-dimethyl-2- (5- (1 H) -tetrazolyl) ethyl, 1-methyl-5- (1 H) tetrazolylmethyl group, 1-ethyl-5- (1 H) -tetrazolylmethyl group, 1-propyl- 5- (1 H) tetrazolylmethyl, group 1-butyl l-5- (1 H) -tetrazolylmethyl, group 1-pentyl-5- (1 H) tetrazolylmethyl, group

-hexi l-5- (1 H) -tetrazolylmethyl, group 1-pheni 1-5- (1 H) tetrazolylmethyl, group 1- (2-fluorophenyl) -5- (1 H) -tetrazolylmethyl, group 1- (3 -fluorophenyl) -5 (IH) -tetrazolylmethyl, group 1- (2,3,4,5,6-pentafluorophenyl) -5- (1 H) -tetrazolylmethyl, group

- (2-chlorophenyl) -5- (1 H) -tetrazolylmethyl, group 1 - (3-chlorophenyl) -5- (1 H) -tetrazolylmethyl, group 1- (2,4,6-trichlorophenyl) -5- ( 1 H) -tetrazolylmethyl, group 1- (2-bromophenyl) -5- (1 H) tetrazolylmethyl, group 1- (2,3-dibromophenyl) -5- (1 H) -tetrazolylmethyl, group 1- (4bromophenyl) - 5- (1 H) -tetrazolylmethyl, group 2- (1-methyl-5- (1 H) -tetrazolyl) ethyl, group 2- (1ethyl-5- (1 H) -tetrazolyl) ethyl, group 2- (1 -prpopyl-5- (1 H) -tetrazolyl) ethyl, group 2- (1-butyl-5

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249/854 (1 H) -tetrazolyl) ethyl, group 2- (1-pentyl-5- (1 H) -tetrazolyl) ethyl, group 2- (1-hexyl-5- (1 H) tetrazolyl) ethyl, group 2- (1-pheni 1-5- (1 H) -tetrazolyl) ethyl, group 2- (1- (2-fluorophenyl) -5- (1 H) tetrazolyl) ethyl, group 2- (1- (3- fluorophenyl) -5- (1 H) -tetrazolyl) ethyl, group 2- (1- (4fluorophenyl) -5- (1 H) -tetrazolyl) ethyl, group 2- (1 - (2-chlorophenyl) -5- ( 1 H) -tetrazolyl) ethyl, group

2- (1- (3-chlorophenyl) -5- (1 H) -tetrazolyl) ethyl, group 2- (1- (4-chlorophenyl) -5- (1 H) -tetrazolyl) ethyl, group 2- (1 - (2-bromophenyl) -5- (1 H) -tetrazolyl) ethyl, group 2- (1- (3-bromophenyl) -5- (1 H) tetrazolyl) ethyl, group 2- (1- (4-bromophenyl) ) -5- (1 H) -tetrazolyl) ethyl or the like.

[0337] A piperidine ring or a 1,2,3,6-tetrahydropyridine ring that is formed by combining R ³² and R ³³ together with the adjacent nitrogen atom via the other carbon atom (the piperidine ring or a ring 1,2,3,6-tetrahydropyridine may have a phenyl group as a substituent, and the phenyl group may have at least one substituent selected from a group consisting of a halogen atom and an unsubstituted or substituted C1-6 alkyl group halogen as a substituent) include a piperidine ring and a 1,2,3,6-tetrahydropyridine ring that can be replaced by a phenyl group on the ring that can be replaced by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom and a C1-6 alkyl group unsubstituted or substituted by halogen as a substituent, for example, a piperidine group, 4-phenylpiperidine group, group 4- (2-fluorophenyl) piperidine, group 4- ( 3-fluorophenyl) piperidine, group 4- ( 3-fluoro-4trifluoromethylphenyl) piperidine, group 4- (3,4,5-trichlorophenyl) piperidine, group 4- (2,3,4,5,6pentafluorophenyl) piperidine, group 4- (2,4-dimethylphenyl) piperidine, group 4- (2,4,6-trimethylphenyl) piperidine, group 4- (2-trifluoromethyl-4-methylphenyl) pipendine, group 4- (4-fluorophenyl) piperidine, group 4- (3,4-difluorophenyl) piperidine, group 4- ( 2chlorophenyl) piperidine, group 4- (3-chlorophenyl) piperidine, group 4- (4-chlorophenyl) piperidine, group 4- (3,4-dichlorophenyl) piperidine, group 4- (2-methylphenyl) piperidine, group 4- ( 3methylphenyl) piperidine, group 4- (4-methylphenyl) piperidine, group 4- (2trifluoromethylphenyl) piperidine, group 4- (3-trifluoromethylphenyl) pipendine, group 4- (4trifluoromethylphenyl) piperidine, group 4-phenyl-1,2,3,3 , 6-tetrahydropyridine, group 4- (2-fluorophenyl) -1,2,3,6-tetrahydropyridine, group 4- (3-fluorophenyl) -1,2,3,6-tetrahydropyridine, group 4- (4-fluorophenyl) - 1,2,3,6-tetrahydropyridine, group 4- (3,4-difluorophenyl) -1,2,3,6

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250/854 tetrahydropyridine, group 4- (2-chlorophenyl) -1,2,3,6-tetrahydropyridine, group 4- (3-chlorophenyl) -

1,2,3,6-tetrahydropyridine, group 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine, group 4- (3,4dichlorophenyl) -1,2,3,6-tetrahydropyridine, group 4 - (2-methylphenyl) -1,2,3,6-tetrahydropyridine, group 4- (3-methylphenyl) -1,2,3,6-tetrahydropyridine, group 4- (4-methylphenyl) -1,2,3 , 6 tetrahydropyridine, group 4- (2-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, group 4- (3trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, group 4- (4-trifluoromethylphenyl) - 1,2,3,6tetrahydropyridine, group 4- (3-fluoro-4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, group 4- (3,4,5-trichlorophenyl) -1,2,3, 6-tetrahydropyridine, group 4- (2,3,4,5,6-pentafluorophenyl) -

1.2.3.6- tetrahydropyridine, group 4- (2,4-dimethylphenyl) -1,2,3,6-tetrahydropyridine, group 4 (2,4,6-trimethylphenyl) -1,2,3,6-tetrahydropyridine, group 4- (2-trifluoromethyl-4-methylphenyl) -

1.2.3.6- tetrahydropyridine or similar.

[0338] Examples of a C3-8 cycloalkenyl group include a cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, cyclooctenyl group or the like.

[0339] A phenyl group (which can be substituted on the phenyl ring by 1 to 5 groups selected from a group consisting of a halogen atom, C16 alkyl group unsubstituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen, C1-4 alkylenedioxy group, C1-6 alkylsulfonyl group, unsubstituted or substituted C1-6 alkylthio group, nitro group and amino group which may have a C1-6 alkanoyl group as a substituent) includes a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group, C1-6 alkoxy group unsubstituted or substituted by halogen, C1-4 alkylenedioxy group, C1-6 alkylsulfonyl group, C1-6 alkylthio group unsubstituted or substituted by halogen, nitro group and amino group that may have 1 to 2 C 1-6 alkanoyl group as a substituent (in the case of a C 1-4 alkylenedioxy group as a substituent, 1 to 3 substituents are preferable)), for example, a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group , group 4-fluorophenyl, group 2-chlorophenyl, group 3-chlorophenyl, group 4-chlorophenyl, group 2-bromophenyl, group 3-bromophenyl, group 4-bromophenyl,

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251/854 group 2-iodophenyl, group 3-iodophenyl, group 4-iodophenyl, group 2,3-difluorophenyl, group 3,4-difluorophenyl, group 3,5-difluorophenyl, group 2,4-difluorophenyl, group 2,6difluorophenyl , 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4,5-trifluorophenyl group, 3,4,5dichlorophenyl , 2,4,6-trifluorophenyl group, 2,3,4,5,6-pentafluorophenyl group, 2,4,6trichlorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4dimethylphenyl group, 2,4,6-trimethylphenyl group, 2-methyl-3-chlorophenyl group, 3-methyl-4-chlorophenyl group, 2-chloro-4-methylphenyl group, 2-methyl-3-fluorophenyl group, 2trifluoromethylphenyl group, 3-trifluoromethylphenyl group , 4-trifluoromethylphenyl group, 2pentafluoroethylphenyl group, 3-pentafluoroethylphenyl group, 4-pentafluoroethylphenyl group, group

2- isopropylphenyl, group 3-isopropylphenyl, group 4-isopropylphenyl, group 2-ter-butylphenyl, group 3-ter-butylphenyl, group 4-ter-butylphenyl, group 2-sec-butylphenyl, group 3-secbutylphenyl, group 4- sec-butylphenyl, group 2-n-heptafluoropropylphenyl, group 3-nheptafluoropropylphenyl, group 4-n-heptafluoropropylphenyl, group 4-pentylphenyl, group 4hexylphenyl, group 2-methoxyphenyl, group 3-methoxyphenyl, group 3-methoxyphenyl, group 3-methoxyphenyl

3-chlorophenyl, 2-fluoro-3-methoxyphenyl group, 2-fluoro-4-methoxyphenyl group, 2,6dimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, 2,3,4-trifluorophenyl group, group 3,4, 5trifluorophenyl, group 2-trifluoromethoxyphenyl, group 3-trifluoromethoxyphenyl, group 4trifluoromethoxyphenyl, group 2-pentafluoroethoxyphenyl, group 3-pentafluoroethoxyphenyl, group 2-pentafluoroethoxyphenyl, group 2-isopropoxyphenyl, 4-isopropoxyphenyl butoxyphenyl, group 3-ter-butoxyphenyl, group 4-terbutoxyphenyl, group 2-sec-butoxyphenyl, group 3-sec-butoxyphenyl, group 4-secbutoxyphenyl, group 2-n-heptafluoropropoxyphenyl, group 3-n-heptafluoropropoxyphenyl, group 4- n-heptafluoropropoxyphenyl, group 4-pentoxiphenyl, group 4-hexyloxyphenyl, group 2,3-methylenedioxyphenyl, group 3,4-methylenedioxyphenyl, group 3-nitrophenyl, group 2,3-dinitrophenyl, group 2,4,6-trinitrophenyl, group 4-nitrophenyl, 3-methylthiophenyl group, 4-methylthiophenyl group, 3-trifluoromethylthiophenyl group , 4-trifluoromethylthiophenyl group, 3-methanesulfonylphenyl group, 4-methanesulfonylphenyl group, 2methanesulfonylphenyl group, 2-aminophenyl group, 2,4-diaminophenyl, 2,4,6triaminophenyl group, 2-acetylaminophenyl group, 3-acetylamin group

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252/854 acetylaminophenyl or the like.

[0340] A benzofuryl group (which can be substituted on the benzofuran ring by at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group and a C1-6 alkoxy group unsubstituted or substituted by halogen) includes a benzofuryl group (which can be substituted on the benzofuran ring by 1 to 3 groups selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and an unsubstituted or substituted halogen C1-6 alkoxy group), for example, an unsubstituted 2-benzofuryl group, 4-fluoro-2-benzofuryl group, 5-fluoro-2-benzofuryl group, 6-fluoro-group

2-benzofuryl, group 7-fluoro-2-benzofuryl, group 4-chloro-2-benzofuryl, group 5-chloro-

2-benzofuryl, 6-chloro-2-benzofuryl group, 7-chloro-2-benzofuryl group, 4bromo-2-benzofuryl group, 5-bromo-2-benzofuryl group, 6-bromo-2-benzofuryl group, group 7- bromo-2-benzofuryl, 4-methyl-2-benzofuryl group, 5-methyl-2-benzofuryl group, 6-methyl-2-benzofuryl group, 7-methyl-2-benzofuryl group, 4-trifluoromethyl-2benzofuryl group, group 5-trifluoromethyl-2-benzofunyl, 6-trifluoromethyl-2-benzofuryl group, 7-trifluoromethyl-2-benzofuryl group, 4-ethyl-2-benzofuryl group, 5-ethyl-2benzofuryl group, 6-ethyl-2-benzofuryl group , 7-ethyl-2-benzofuryl group, 4pentafluoroethyl-2-benzofuryl group, 5-pentafluoroethyl-2-benzofuryl group, 6pentafluoroethyl-2-benzofuryl group, 7-pentafluoroethyl-2-benzofuryl group, 4-methyloxy-2benzofuryl group 5-methoxy-2-benzofuryl, 6-methoxy-2-benzofuryl group, 7methoxy-2-benzofuryl group, 4-trifluoromethoxy-2-benzofunla group, 5-trifluoromethoxy-2benzofuryl group, 6-trifluoromethoxy-2-benzofunla group, group 7-trifluoromethoxy-2benzofuryl, gru po 4-isopropyl-2-benzofuryl, 5-isopropyl-2-benzofuryl group, 6isopropyl-2-benzofuryl group, 7-isopropyl-2-benzofuryl group, 4-hexyl-2-benzofuryl group, 5-hexyl-2- group benzofuryl, 6-hexyl-2-benzofuryl group, 7-hexyl-2-benzofuryl group, 4-ethoxy-2-benzofuryl group, 5-ethoxy-2-benzofuryl group, 6-ethoxy-2-benzofuryl group, group 7- ethoxy-2-benzofuryl, group 4-fluoro-5-trifluoromethyl-2-benzofunla, group 6fluoro-5-trifluoromethyl-2-benzofuryl, group 7-fluoro-5-trifluoromethyl-2-benzofunla, group

4-chloro-5-trifluoromethyl-2-benzofunla, group 6-chloro-5-trifluoromethyl-2-benzofunla,

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253/854 7-chloro-5-trifluoromethyl-2-benzofunla group, 4-chloro-5-trifluoromethoxy-2benzofuryl group, 6-chloro-5-trifluoromethoxy-2-benzofunla group, 7-chloro-5trifluoromethoxy-2-benzofuryl group , 3-benzofuryl group, 4-fluoro-3-benzofuryl group, group

5- fluoro-3-benzofuryl, group 6-fluoro-3-benzofuryl, group 7-fluoro-3-benzofuryl, group 4-chloro-3-benzofuryl, group 5-chloro-3-benzofuryl, group 6-chloro-3 -benzofuryl, 7-chloro-3-benzofuryl group, 4-bromo-3-benzofuryl group, 5-bromo-3-benzofuryl group, 6-bromo-3-benzofuryl group, 7-bromo-3-benzofuryl group, 4-methyl group -

3-benzofuryl, 5-methyl-3-benzofuryl group, 6-methyl-3-benzofuryl group, 7-methyl-

3-benzofuryl, group 4-trifluoromethyl-3-benzofunla, group 5-trifluoromethyl-3-benzofunla, group 6-trifluoromethyl-3-benzofunla, group 7-trifluoromethyl-3-benzofuryl, group 4-ethyl-3benzofuryl, group 5- ethyl-3-benzofuryl, group 6-ethyl-3-benzofuryl, group 7-ethyl-3-benzofuryl, group 4-pentafluoroethyl-3-benzofuryl, group 5-pentafluoroethyl-3-benzofuryl, group 6-pentafluoroethyl-3-benzofuryl, group 7-pentafluoroethyl-3benzofuryl, 4-methoxy-3-benzofuryl group, 5-methoxy-3-benzofuryl group, 6methoxy-3-benzofuryl group, 7-methoxy-3-benzofuryl group, 4-trifluoromethoxy-3benzofuryl group, group 5- trifluoromethoxy-3-benzofuryl, group 6-trifluoromethoxy-3benzofuryl, group 7-trifluoromethoxy-3-benzofunla, group 4-isopropyl-3-benzofuryl, group 5-isopropyl-3-benzofuryl, group 6-isopropyl-3-benzofuryl, group 6 7-isopropyl-3benzofuryl, 4-hexyl-3-benzofuryl group, 5-hexyl-3-benzofuryl group, 6-hexyl-3benzofuryl group, 7-hexyl-3-benzofuryl group, 4-ethoxy-3-benzofuryl group, group 5-ethoxy -3benzofuryl, group 6-ethoxy-3-benzofuryl, group 7-ethoxy-3-benzofuryl, group 4-fluoro-5trifluoromethyl-3-benzofuryl, group 6-fluoro-5-trifluoromethyl-3-benzofunla, group 7fluoro-5- trifluoromethyl-3-benzofuryl, group 4-chloro-5-trifluoromethyl-3-benzofunla, group

6- chloro-5-trifluoromethyl-3-benzofunla, group 7-chloro-5-trifluoromethyl-3-benzofunla, group 4-chloro-5-trifluoromethoxy-3-benzofunla, group 6-chloro-5-trifluoromethoxy-3benzofuryl, group 6,7-dichloro-5-trifluoromethoxy-3-benzofunla, 5,6,7-trichloro-2benzofuryl group, 7-chloro-5-trifluoromethoxy-3-benzofunla group or the like.

[0341] A furyl group (which can be substituted on the furan ring with a phenyl group that can have a halogen atom as a substituent) includes a furyl group (which can be replaced on the furan ring with 1 to 3 phenyl groups that

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254/854 may have from 1 to 5 halogen atoms as a substituent), for example, a 2-furyl group, 3,5-diphenyl-2-furyl group, 2,4,5-triphenyl-3-furyl group, group 5- (4-chlorophenyl) -2-furyl, group 4- (4-fluorophenyl) -2-furyl, group 4- (2,3,4,5,6-pentafluorophenyl) 2-furyl, group 3- (4- bromophenyl) -2-furyl, group 3-furyl, group 5- (2,4-dichlorophenyl) -3-furyl, group 4- (2,4,6-trichlorophenyl) -3-furyl, group 3- (4-iodophenyl) -3-furila or similar. [0342] A phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom; C1-6 alkyl group unsubstituted or substituted by halogen; C3-8 cycloalkoxy group; group hydroxyl; C1-8 alkoxy group unsubstituted or substituted by halogen; C3-8 cycloalkoxy group; C1-4 alkylenedioxy group; cyano group; nitro group; C2-6 alkenyl phenyl group; C2-6 alkanoyloxy group; amino group presenting a group C1-6 alkanoyl as a substituent; C1-6 alkylsulfonylamino group; C1-6 alkoxy phenyl group; phenoxy group; amino group having at least one C1-6 alkyl group as a substituent; amino group which may have at least one phenyl group as a substituent; C1-6 alkoxy amino group which may have at least one C1-6 alkyl group in the amino group as a substituent; C1-6 alkoxycarbonyl group; C1-6 alkoxycarbonyl group C1-6 alkoxy; C1-6 alkylthio group; pyrrolyl; group imidazolyl, piperidyl group; morpholino group; pyrrolidinyl group; thienyl group; benzofuryl group; piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from a group consisting of a C1-6 alkyl group, phenyl C1-6 alkyl group and benzoyl group which can have at least one C1-6 alkyl group as a substituent); quinolyl group that can be substituted on the quinoline ring by at least one group selected from a group consisting of a C1-6 alkoxy group and an oxo group; a piperidylcarbonyl group that can be substituted on the piperidine ring by a carbostyryl group; and a triazolyl group) includes a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom; C16 alkyl group unsubstituted or substituted by halogen; C3-8 cycloalkoxy group; hydroxyl group; C1-8 alkoxy group unsubstituted or substituted by halogen; C3-8 cycloalkoxy group; C1-4 alkylenedioxy group; cyano group; nitro group; C2-6 phenyl alkenyl group;

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255/854 C2-6 alkanoyloxy; amino group which may have 1 to 2 C 1-6 alkanoyl groups as a substituent; C 1-6 alkylsulfonylamino group; phenyl C 1-6 alkoxy group; phenoxy group; amino group having 1 to 2 C 1-6 alkyl groups as a substituent; amino group having 1 to 2 phenyl groups as a substituent; C1-6 alkoxy amino group which may have 1 to 2 C1-6 alkyl groups in the amino group as a substituent; alkoxycarbonyl group Ci-e; C1-6 alkoxycarbonyl group C1-6 alkoxy; C 1-6 alkylthio group; pyrrolyl group; imidazolyl group; piperidinyl group; morpholino group; pyrrolidinyl group; thienyl group; benzofuryl group; piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from a group consisting of a C1-6 alkyl group, phenyl C1-6 alkyl group and benzoyl group which can have 1 to 3 C1-6 alkyl groups as a substituent); quinolyl group which can be substituted on the quinoline ring by at least one group selected from a group consisting of a C1-6 alkoxy group and an oxo group; a piperidylcarbonyl group that can be substituted on the piperidine ring by a carbostyryl group; and a triazolyl group (in the case of 1 to 3 C 1-4 alkylenedioxy groups as a substituent, 1 to 3 substituents are preferred)), for example, a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, group 4- fluorophenyl, group 2-chlorophenyl, group 3-chlorophenyl, group 4-chlorophenyl, group 2-bromophenyl, group 3-bromophenyl, group 4-bromophenyl, group 2-iodophenyl, group 3-iodophenyl, group 4-iodophenyl, group 2, 3-difluorophenyl, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2,4-difluorophenyl group, 2,6-difluorophenyl group, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group , 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 2,3,4trifluorophenyl group, 3,4,5-trifluorophenyl group, 3,4,5-trichlorophenyl group, 2,4,6trifluorophenyl group, group 2, 3,4,5,6-pentafluorophenyl, group 2,4,6-trichlorophenyl, 2-fluoro-4 chlorophenyl, group 2-fluoro-4-bromophenyl, 3-fluoro-4-chlorophenyl, group 2-methylphenyl, group 3- methylphenyl, 4-methylphenyl group, 2,6-dime group tilphenyl, 2,4,6-trimethylphenyl group, 2-methyl-3-chlorophenyl group, 3-methyl-4-chlorophenyl group, 2-chloro-4methylphenyl group, 2-methyl-3-fluorophenyl group, 2-trifluoromethylphenyl group, 3trifluoromethylphenyl group , 4-trifluoromethylphenyl group, 3,5-di (trifluoromethyl) phenyl, 3,4di (trifluoromethyl) phenyl group, 2,4-di (trifluoromethyl) phenyl group, 2-pentafluoroethylphenyl group,

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256/854 group 3-pentafluoroethylphenyl, group 4-pentafluoroethylphenyl, group 2-isopropylphenyl, group 3-isopropylphenyl, group 4-isopropylphenyl, group 2-ter-butylphenyl, group 3-terbutilphenyl, group 4-teri-butiI sec-butylphenyl, group 3-sec-butylphenyl, group

4-sec-butylphenyl, group 4-n-butylphenyl, group 4-n-pentylphenyl, group 4-n-hexylphenyl, group 2-n-heptafluoropropylphenyl, group 3-n-heptafluoropropylphenyl, group 4-nheptafluoropropylphenyl, group 4- , 4-hexylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-methoxy-3-chlorophenyl group, 2fluoro-3-methoxyphenyl group, 2-fluoro-4-methoxyphenyl group, 4-cyclopropylphenyl group , 4cyclobutylphenyl group, 4-cyclopentylphenyl group, 4-cyclohexylphenyl group, 4-cycloheptylphenyl group, 4-cyclooctylphenyl group, 2,6-dimethoxyphenyl group, 2trifluoromethoxyphenyl group, 3-trifluoromethoxyphenyl group, 4-trifluoromethoxy group trifluoromethoxy) phenyl, group 3,5-di (trifluoromethoxy) phenyl, group 2,4di (trifluoromethoxy) phenyl, group 2-pentafluoroethoxyphenyl, group 3-pentafluoroethoxyphenyl, group 4-pentafluoroethoxyphenyl, group 2-isopropoxyphenyl, group 3-isopropyl 4-isopropoxyphenyl, group 2-ter-butoxyphenyl, group 3-ter-butoxyphenyl a, 4-terbutoxyphenyl group, 2-sec-butoxyphenyl group, 3-sec-butoxyphenyl group, 4-secbutoxyphenyl group, 4-n-hexyloxyphenyl group, 4-n-heptyloxyphenyl, 4-n-octyloxyphenyl group, group

2- n-heptafluoropropoxyphenyl, group 3-n-heptafluoropropoxyphenyl, group 4-nheptafluoropropoxyphenyl, group 4-cyclopropoxyphenyl, group 4-cyclobutoxyphenyl, group

4-cyclopentoxiphenyl, 4-cyclohexyloxyphenyl group, 4-cycloheptyloxyphenyl group, 4cyclooctyloxyphenyl group, 4-pentoxiphenyl group, 4-hexyloxyphenyl group, 2-hydroxyphenyl, group

3-hydroxyphenyl, 4-hydroxyphenyl group, 2,4-dihydroxyphenyl group, 2,4,6-trihydroxyphenyl group, 2-methoxy-3-chlorophenyl group, 2-fluoro-3-hydroxyphenyl group, 2fluoro-4-hydroxy-phenyl group, 2,3-methylenedioxyphenyl group, 3,4-methylenedioxyphenyl group, 2,3-ethylenedioxyphenyl group, 3,4-ethylenedioxyphenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2,3-dicianophenyl group, group 2 , 4,6-tricianophenyl, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2,4-dinitrophenyl group, 2,4,6-trinitrophenyl group, 2-cinamylphenyl group, 3-cinamylphenyl group, 4cinamylphenyl group , 2-acetyloxyphenyl group, 3-acetyloxyphenyl group, 2-aminophenyl group, 2,4-diaminophenyl group, 2,4,6-triaminophenyl group, 4-acetyloxyphenyl group, group 2

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257/854 propionyloxyphenyl, 3-propionyloxyphenyl group, 4-propionyloxyphenyl group, 2butyryloxyphenyl group, 3-butyryloxyphenyl group, 4-butyryloxyphenyl group, 4pentanoyloxyphenyl group, 4-hexanoyloxyphenyl group, 4-acetylaminophenyl group, group 4-acetylaminophenyl group 2-propionylaminophenyl, 3propionylaminophenyl group, 4-propionylaminophenyl group, 2-butyrylaminophenyl group, 3butyrylaminophenyl group, 4-butyrylaminophenyl group, 4-pentanoylaminophenyl group, 4hexanoylaminophenyl group, 2-methanesulfonylaminophenyl group 3-benzyloxyphenyl, group 4-benzyloxyphenyl, group 2- (2-phenylethoxy) phenyl, group 3- (2-phenylethoxy) phenyl, group 4- (2-phenyloxy) phenyl, group 2- (3-phenylpropoxy) phenyl, group 3- (3 -phenylpropoxy) phenyl, group 4- (3-phenylpropoxy) phenyl, group

2- (4-phenylbutoxy) phenyl, group 3- (4-phenylbutoxy) phenyl, group 4- (4-phenylbutoxy) phenyl, group

2- (5-phenylpentoxy) phenyl, group 3- (5-phenylpentoxy) phenyl, group 4- (5-phenylpentoxy) phenyl, group 2- (6-phenylexoxy) phenyl, group 3- (6-phenylexoxy) phenyl, group 4- (6-phenylexoxy) phenyl, group 2-phenoxyphenyl, group 3-phenoxyphenyl, group 4-phenoxyphenyl, group 2-methylaminophenyl, group 3-ethylaminophenyl, group 4-propylaminophenyl, group 2-nbutilaminophenyl, group 3-n-pentylaminophenyl, group 4-n-hexylaminophenyl, 2dimethylaminophenyl group, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group, 2diethylaminophenyl group, 3-diethylaminophenyl group, 4-diethylaminophenyl group, 2-di- (npropyl) aminophenyl group, 3-di- (n- propyl) aminophenyl, group 4-di- (n-propyl) aminophenyl, group 3-phenylaminophenyl, group 2-diphenylaminophenyl, group 3-diphenylaminophenyl, group

4-diphenylaminophenyl, group 2- (2-methylaminoethoxy) phenyl, group 3-ethylaminomethoxyphenyl, group 2- (2-dimethylaminoethoxy) phenyl, group 3- (2-dimethylaminoethoxy) phenyl, group 4- (2-

dimethylaminoethoxy) phenyl, group 2- (3-dimethylaminopropoxy) phenyl, group 3- (3- dimethylaminopropoxy) phenyl, group 4- (3-dimethylaminopropoxy) phenyl, group 4- (4- dimethylaminobutoxy) phenyl, group 4- (5-dimethylaminopentoxy) phenyl, group 4- (6- dimethylaminohexyloxy) phenyl, group 2- (2-diethylaminoethoxy) phenyl, group 3- (2- diethylaminoethoxy) phenyl, group 4- (2-diethylaminoethoxy) phenyl, group 2- (3- diethylaminopropoxy) phenyl, group 3- (3-diethylaminopropoxy) phenyl, group 4- (3- diethylaminopropoxy) phenyl, group 4- (4-diethylaminobutoxy) phenyl, group 4- (5-

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258/854 diethylam inopentoxy) phenyl, group 4- (6-diethylaminohexyloxy) phenyl, group 2metoxicarbonylphenyl, group 3-methoxycarbonylphenyl, group 4-methoxycarbonylphenyl, group 2-ethoxycarbonylphenyl, group 3-ethoxycarbonylphenyl, group 4-group 4-group 3-propoxycarbonyl) phenyl, group 4- (4-butoxycarbonyl) phenyl, group 4- (5pentoxicarbonyl) phenyl, group 4- (6-hexyloxycarbonyl) phenyl, group 2-methoxycarbonylmethoxyphenyl, group 3-methoxycarbonylmethoxyphenyl, group 4methoxycarbonylmethoxyphenyl, group 2 group 3etoxicarbonylmethoxyphenyl, group 4-ethoxycarbonylmethoxyphenyl, group 4- (3propoxycarbonyl) methoxyphenyl, group 4- (4-butoxycarbonyl) methoxyphenyl, group 4- (5pentoxicarbonyl) methoxyphenyl, group 4- (6-hexyloxycarbonyl) methoxyphenyl, group 4- (4 phenyl, group 4- (2-ethoxycarbonyl) ethoxyphenyl, group 4- (2- (3-propoxycarbonyl) ethoxy) phenyl, group 4- (2- (4-butoxycarbonyl) ethoxy) phenyl, group 4- (2- (5pentoxicarbonyl) ethoxy ) phenyl, group 4- (2- (6-hexyloxycarbon il) ethoxy) phenyl, group 4- (3-methoxycarbonylpropoxy) phenyl, group 4- (3- (2-ethoxycarbonyl) propoxy) phenyl, group 4- (3- (3 (propoxycarbonyl) propoxy) phenyl, group 4- (3- (4 -butoxycarbonyl) propxy) phenyl, group 4- (3 (5-pentoxycarbonyl) propoxy) phenyl, group 4- (3- (6-hexyloxycarbonyl) propoxy) phenyl, group 4- (4-methoxycarbonylbutoxy) phenyl, group 4- ( 4- (2-ethoxycarbonyl) butoxy) phenyl, group 4- (5methoxycarbonylpentoxy) phenyl, group 4- (5- (2-ethoxycarbonyl) pentoxy) phenyl, group 4- (6- (2ethoxycarbonyl) hexyloxy) phenyl, group 2- methylthiophenyl, group 3-methylthiophenyl, group 4methylthiophenyl, group 4-ethylthiophenyl, group 4-n-propylthiophenyl, group 4-isopropylthiophenyl, group 4-n-butylthiophenyl, group 4-ter-butylthiophenyl, group 4-n-pentylthiophenyl, group -nhexylthiophenyl, group 2- (1-pyrrolyl) phenyl, group 3- (1-pyrrolyl) phenyl, group 4- (1-pyrrolyl) phenyl, group 2- (1-imidazolyl) phenyl, group 3- (1-imidazolyl) phenyl , group 4- (1imidazolyl) phenyl, group 2-piperidinophenyl, group 3-piperidinophenyl, group 4piperidi nophenyl, group 4-morpholinophenyl, group 3-morpholinophenyl, group 2morpholinophenyl, group 2- (1-pyrrolidinyl) phenyl, group 3- (1-pyrrolidinyl) phenyl, group 4- (1pyrrolidinyl) phenyl, group 2- (2-thienyl ) phenyl, group 3- (2-thienyl) phenyl, group 4- (2-thienyl) phenyl, group 2- (2-benzofuryl) phenyl, group 3- (2-benzofuryl) phenyl, group 4- (2-benzofuryl ) phenyl, group 2- (1-piperazinyl) phenyl, group 3- (1-piperazinyl) phenyl, group 4- (1-piperazinyl) phenyl, group 2- (4-methyl-1-piperazinyl) phenyl, group 3- (4-methyl-1-piperazinyl) phenyl, group 4- (4

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259/854 methyl-1-piperazinyl) phenyl, group 4- (4-ethyl-1-piperazinyl) phenyl, group 4- (4-n-propyl-1piperazinyl) phenyl, group 4- (4-isopropyl-1-piperazinyl ) phenyl, group 4- (4-n-butyl-1 piperazinyl) phenyl, group 4- (4-ter-butyl-1-piperazinyl) phenyl, group 4- (4-n-pentyl-1piperazinyl) phenyl, group 4 - (4-n-hexyl-1-piperazinyl) phenyl, group 4- (4-benzyl-1piperazinyl) phenyl, group 4- (4- (2-phenethyl) -1-piperazinyl) phenyl, group 4- (4- (3-phenylpropyl) -1 piperazinyl) phenyl, group 4- (4- (4-pheniIbuti 1) -1-piperazinyl) phenyl, group 4- (4- (5-pheniIpentiI) 1 -piperazinyl) phenyl, group 4- (4- (6-phenylexyl) -1-piperazinyl) phenyl, group 4- (4-benzoyl-1piperazinyl) phenyl, group 4- (4- (2-methylbenzoyl) -1-piperazinyl) phenyl, group 4- (4 - (2,3-dimethylbenzoyl) -1-piperazinyl) phenyl, group 4- (4- (2,4,6-trimethylbenzoyl 1) -1 piperazinyl) phenyl, group 4- (4- (3-methylbenzoyl ) -1-piperazinyl) phenyl, group 4- (4- (4-methylbenzoyl) -1-piperazinyl) phenyl, group 4- (4- (4-ethylbenzoyl) -1 -piperazinyl) phenyl, group 4- (4- ( 4-isopropylbenzoyl) - 1-piperazinyl) phenyl, group 4- (4- (4-n-butylbenzoyl) -1 piperazinyl) phenyl, group 4- (4- (4-n-pentylbenzoyl) -1-piperazinyl) phenyl, group 4 - (4- (4-nhexylbenzoyl) -1-piperazinyl) phenyl, group 3- (2-quinolyl) phenyl, 4- (4,5,6-trimethoxy-3quinolyl) phenyl, group 4- (6-methoxy-2 -quinolyl) phenyl, group 2- (5,6-dimethoxy-4quinolyl) phenyl, group 3- (2-oxo-3-quinolyl) phenyl, group 4- (2-oxo-3-quinolyl) phenyl, group

3- (5-methoxy-2-oxo-3-quinolyl) phenyl, group 4- (5-methoxy-2-oxo-3-quinolyl) phenyl, group 3 (6-methoxy-2-oxo-7-quinolyl) phenyl, group 4- (6-methoxy-2-oxo-3-quinolyl) phenyl, group 3- (7-methoxy-2-oxo-6-quinolyl) phenyl, group 4- (7-methoxy-2-oxo-8- quinolyl) phenyl, group 3- (8-methoxy-2-oxo-3-quinolyl) phenyl, group 4- (8-methoxy-2-oxo-3-quinolyl) phenyl, group 3- (5,6diethoxy-2-oxo- 4-quinolyl) phenyl, group 4- (5-ethoxy-2-oxo-3-quinolyl) phenyl, group 3- (6ethoxy-2-oxo-5-quinolyl) phenyl, group 4- (6-ethoxy-2- oxo-3-quinolyl) phenyl, group 3- (7-ethoxy-

2- oxo-3-quinolyl) phenyl, group 4- (7-ethoxy-2-oxo-3-quinolyl) phenyl, group 3- (8-ethoxy-2-oxo-

3- quinolyl) phenyl, group 4- (8-ethoxy-2-oxo-3-quinolyl) phenyl, group 3- (1- piperidinylcarbonyl) phenyl, group 4- (4- (carbostyryl-1-yl) piperidinyl-1 -carbonyl) phenyl, group

4- (1,2,4-triazol-1-yl) phenyl or the like.

[0343] A naphthyl group that can be substituted on the naphtalne ring by a group selected from a group consisting of a halogen atom, a C1-6 alkoxy group unsubstituted or substituted by halogen, and an amino group that may have an alkyl group C1-6 as a substituent includes a naphthyl group that can

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260/854 be substituted on the naphtalne ring by 1 to 3 groups selected from a group consisting of a halogen atom, a C1-6 alkoxy group unsubstituted or substituted by halogen and an amino group which may have 1 to 2 groups C1-6alkyl as a substituent, for example, a 1-naphthylmethyl group, 2- (2naphthyl) ethyl group, 1- (3-naphthyl) ethyl group, 3- (4-naphthyl) propyl group, group 4- (5 -naphthyl) butyl, group 5- (6-naphthyl) pentyl, group 6- (7-naphthyl) hexyl, group 2-methyl-3- (8-naphthyl) propyl, group 1,1-dimethyl-2- (3 -naphthyl) ethyl, 2-fluoro-1-naphthyl group, 2-chloro-1-naphthyl group, 2-bromo-1-naphthyl group, 3-fluoro-1-naphthyl group, 3-chloro-1-naphthyl group, 3bromo-1-naphthyl group, 4-fluoro-1-naphthyl group, 4-chloro-1-naphthyl group, 4-bromo-1naphthyl group, 5-fluoro-1-naphthyl group, 5-chloro-1-naphthyl group, group 5-bromo-1-naphthyl, group

6-fluoro-1-naphthyl, 6-chloro-1-naphthyl group, 6-bromo-1-naphthyl group, 7-fluoro-1-naphthyl group, 7-chloro-1-naphthyl group, 7-bromo-1-naphthyl group , group 1-fluoro-2-naphthyl, group

8-fluoro-1-naphthyl, 8-chloro-1-naphthyl group, 8-bromo-1-naphthyl group, 1-fluoro-2naphthyl group, 1-chloro-2-naphthyl group, 1-bromo-2-naphthyl group , group 3-fluoro-2-naphthyl, group

3-chloro-2-naphthyl, 3-bromo-2-naphthyl group, 4-fluoro-2-naphthyl group, 4-chloro-2naphthyl group, 4-bromo-2-naphthyl group, 4-dimethylamino-1-naphthyl group , 2-methoxy-1-naphthyl group, 3-methoxy-1-naphthyl group, 4-methoxy-1-naphthyl group, 5-methoxy-1-naphthyl group, 6-methoxy-1-naphthyl group, 7-methoxy-1 group -naftila, 8-methoxy-1-naphthyl group, 2trifluoromethoxy-1-naphthyl group, 3-trifluoromethoxy-1-naphthyl group, 4-trifluoromethoxy-1naftyl group, 5-trifluoromethoxy-l-naftyl group, 6-trifluoroxy group -naftila, 7trifluoromethoxy-1-naphthyl group, 8-trifluoromethoxy-1-naphthyl group, 3-amino-2-naphthyl group, 2-methylamino-1-naphthyl group, 4-ethylamino-2-naphthyl group, 5-propylamino group -1naphthyl, 6-n-butylamino-2-naphthyl group, 7-n-pentylamino-1-naphthyl group, 8hexylamino-2-naphthyl group, 2,3-dichloro-1-naphthyl group, 2,4,6- trichloro-1-naphthyl, 2-chloro-4-trifluoromethoxy-1-naphthyl group, 2-chloro-6-dimethylamino-1-naphthyl group, 2-dimethylamino-1-naphthyl group, 3-dimethylamino-1-naphthyl group tila, 4-dimethylamino-1-naphthyl group, 5-dimethylamino-1-naphthyl group, 6-dimethylamino-1-naphthyl group, 7-dimethylamino- group

1-naphthyl, 8-dimethylamino-1-naphthyl group, 1-methoxy-2-naphthyl group, 3-methoxy-2naphthyl group, 4-methoxy-2-naphthyl group, 5-methoxy-2-naphthyl group, group 6- methoxy-2-naphthyl, 7-methoxy-2-naphthyl group, 8-methoxy-2-naphthyl group, l-trifluoromethoxy-2-naphthyl group,

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261/854 group 3-trifluoromethoxy-2-naphthyl, group 4-trifluoromethoxy-2-naphthyl, group 5trifluoromethoxy-2-naphthyl, group 6-trifluoromethoxy-2-naphthyl, group 7-trifluoromethoxy-2naphthyl, group 8-trifluoromethane -naftila, 1-dimethylamino-2-naphthyl group, 3dimethylamino-2-naphthyl group, 4-dimethylamino-2-naphthyl group, 5-dimethylamino-2-naphthyl group, 6-dimethylamino-2-naphthyl group, 7-dimethylamino group -2-naphthyl, 8-dimethylamino-

2-naphthyl or similar.

[0344] A biphenylyl group (which can be substituted on the biphenylyl ring by at least one group selected from a group consisting of a halogen atom, a C1-9 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) includes a biphenylyl group (which can be substituted on the biphenylyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, a C1-9 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group not substituted or substituted by halogen), for example, a 3-biphenylyl group, 4biphenylyl group, 2'-fluoro-3-biphenylyl group, 3'-fluoro-3 group -biphenylyl, group 4'-fluoro-3biphenylyl, group 3 ', 4'-difluoro-3-biphenylyl, group 3', 4 ', 5'-trichloro-3-biphenylyl, group 2', 3 ', 4', 5 ', 6'-pentafluoro-4-biphenylyl, group 2'-fluoro-3', 4'-ditrifluoromethyl-3-biphenylyl, group 2 ', 4'-ditrifluoro-3-biphenylyl, group 3 ', 5'-fluoro-3-biphenylyl, group 2'-chloro-3biphenylyl, group 3'-chloro-3-biphenylyl, group 4'-chloro-3-biphenylyl, group 3', 4'-dichloro-3biphenylyl, group 2 ', 4'-dichloro-3-biphenylyl, group 3', 5'-dichloro-3-biphenylyl, group 2'-methyl-3biphenylyl, group 3'-methyl-3-biphenylyl, group 4'-methyl- 3-biphenylyl, group 3 ', 4'-dimethyl-3biphenylyl, group 2', 4'-dimethyl-3-biphenylyl, group 3 ', 5'-dimethyl-3-biphenylyl, group 2'trifluoromethyl-3-biphenylyl, 3'-trifluoromethyl-3-biphenylyl group, 4'-trifluoromethyl-3biphenylyl group, 3 ', 4'-ditrifluoromethyl-3-biphenylyl group, group 2', 4'-ditrifluoromethyl-3-biphenylyl, group 3 ', 5' -ditrifluoromethyl-3-biphenylyl, group 2'-methoxy-3-biphenylyl, group 3'-methoxy-3biphenylyl, group 4'-methoxy-3-biphenylyl, group 3 ', 4'-dimethoxy-3-biphenylyl, group 2 ', 4'dimethoxy-3-biphenylyl, group 3', 4 ', 5'-trimethoxy-3-biphenylyl, group 3', 5'-dimethoxy-3-biphenylyl, group 2'-trifluoromethoxy-3-biphenylyl, group 3'-trifluoromethoxy-3-biphenylyl, group 4'trifluoromethoxy-3-biphenylyl, g group 3 ', 4'-ditrifluoromethoxy-3-biphenylyl, group 2', 4'ditrifluoromethoxy-3-biphenylyl, group 3 ', 5'-ditrifluoromethoxy-3-biphenylyl, group 2'-fluoro-4

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262/854 biphenylyl, group 3'-fluoro-4-biphenylyl, group 4'-fluoro-4-biphenylyl, group 3 ', 4'-difluoro-4biphenylyl, group 2', 4'-difluoro-4-biphenylyl, group 3 ', 5'-difluoro-4-biphenylyl, group 2'-chloro-

4-biphenylyl, group 3'-chloro-4-biphenylyl, group 4'-chloro-4-biphenylyl, group 3 ', 4'-dichloro-4biphenylyl, group 2', 4'-dichloro-4-biphenylyl, group 3 ', 5'-dichloro-4-biphenylyl, group 2'-methyl-4biphenylyl, group 3'-methyl-4-biphenylyl, group 4'-methyl-4-biphenylyl, group 4'-ethyl-4-biphenylyl, group 4'-n-propyl-4-biphenylyl, group 4'-n-butyl-4-biphenylyl, group 4'-n-pentyl-4-biphenylyl, group 4'-n-hexyl-4-biphenylyl, group 4 ' -n-heptyl-4-biphenylyl, group 4'-n-octyl-4-biphenylyl, group 4'-n-nonyl-4-biphenylyl, group 3 ', 4'-dimethyl-4-biphenylyl, group 2', 4'-dimethyl-4biphenylyl, group 3 ', 5'-dimethyl-4-biphenylyl, group 3', 4 ', 5'-trimethyl-4-biphenylyl, group 2'trifluoromethyl-4-biphenylyl, group 3'-trifluoromethyl -4-biphenylyl, 4'-trifluoromethyl-4biphenylyl group, 3 ', 4'-ditrifluoromethyl-4-biphenylyl group, group 2', 4'-ditrifluoromethyl-4-biphenylyl, group 3 ', 5'-ditrifluoromethyl-4- biphenylyl, 2'-methoxy-4-biphenylyl group, 3'-methoxy-4biphenylyl group, 4'-methoxy-4-biphenylyl group, 3 ', 4'-dimethoxy group -4-biphenylyl, group 2 ', 4'dimethoxy-4-biphenylyl, group 3', 4'-dimethoxy-2'-chloro-4-biphenylyl, group 3 ', 5'-dimethoxy-4biphenylyl, group 2'- trifluoromethoxy-4-biphenyl yl, group 3'-trifluorom ethoxy-4-biphenyl, group 4'-trifluoromethoxy-4-biphenylyl, group 3 ', 4'-ditrifluoromethoxy-4-biphenylyl, group 2', 4 'ditrifluoromethoxy-4-biphenylyl, group 3', 5'-ditrifluoromethoxy-4-biphenylyl or the like.

[0345] A benzothienyl group (which can be substituted on the benzothiophene ring by at least one group selected from a group of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or substituted by halogen) includes a benzothienyl group (which can be substituted on the benzothiophene ring by 1 to 3 groups selected from a halogen atom group, a C1-6 alkyl group unsubstituted or substituted by halogen and a C1 alkoxy group -6 unsubstituted or substituted by halogen), for example, a 2-benzothienyl group, 3-benzothienyl group, 3-methyl-2-benzothienyl group, 2-methyl-3-benzothienyl group, 4-fluoro-2-benzothienyl group , 5-fluoro-2-benzothienyl group, 4,5,6-trichloro-2-benzothienyl group, 6-fluoro-2-benzothienyl group, group

7-fluoro-2-benzothienyl, 4-chloro-2-benzothienyl group, 5-chloro-2-benzothienyl group, 6-chloro-2-benzothienyl group, 7-chloro-2-benzothienyl group, 4-bromo-2benzothienyl group , 5-bromo-2-benzothienyl group, 6-bromo-2-benzothienyl group, group 7

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263/854 bromo-2-benzothienyl, 5-methyl-2-benzothienyl group, 6-methyl-2-benzothienyl group, 7-methyl-2-benzothienyl group, 4-trifluoromethyl-2-benzothienyl group, 5trifluoromethyl-2- group benzothienyl, 6-trifluoromethyl-2-benzothienyl group, 7-trifluoromethyl-2benzothienyl, 4-ethyl-2-benzothienyl group, 5-ethyl-2-benzothienyl group, 6-ethyl-2benzothienyl group, 7-ethyl-2-benzothienyl group , 4-pentafluoroethyl-2-benzothienyl group, group

5-pentafluoroethyl-2-benzothienyl, 6-pentafluoroethyl-2-benzothienyl group, 7pentafluoroethyl-2-benzothienyl group, 4-methoxy-2-benzothienyl group, 5-methoxy-2benzothienyl group, 6-methoxy-2-benzothienyl group, group 7-methoxy-2-benzothienyl, 4trifluoromethoxy-2-benzothienyl group, 5-trifluoromethoxy-2-benzothienyl group, 6trifluoromethoxy-2-benzothienyl group, 7-trifluoromethoxy-2-benzothienyl group, 4-fluoro-3-methyl-2 group -benzothienyl, 5-fluoro-3-methyl-2-benzothienyl group, 6-fluoro-3-methyl-2benzothienyl group, 7-fluoro-3-methyl-2-benzothienyl group, 4-chloro-3-methyl-2benzothienyl group , 5-chloro-3-methyl-2-benzothienyl group, 6-chloro-3-methyl-2-benzothienyl group, 7-chloro-3-methyl-2-benzothienyl group, 4-bromo-3-methyl-2benzothienyl group, group 5-bromo-3-methyl-2-benzothienyl, 6-bromo-3-methyl-2benzothienyl group, 7-bromo-3-methyl-2-benzothienyl group, 5-methyl-3-methyl-2benzothienyl group, group 6- methyl-3-methyl-2-benzothienyl, 7-methyl-3-methyl-2benzothienyl group, 3,4,6-trimethyl-2-benzothi group enyl, 4,5,6-trimethoxy-2-benzothienyl group, 4-trifluoromethyl-3-methyl-2-benzothienyl group, 5-trifluoromethyl-3-methyl-2-benzothienyl group, 6-trifluoromethyl-3-methyl-2- group benzothienyl, 7-trifluoromethyl-3methyl-2-benzothienyl group, 4-ethyl-3-methyl-2-benzothienyl group, 5-ethyl-3-methyl-2benzothienyl group, 6-ethyl-3-methyl-2-benzothienyl group, 7-ethyl-3-methyl-2-benzothienyl group, 4-pentafluoroethyl-3-methyl-2-benzothienyl group, 5-pentafluoroethyl-3-methyl-2benzothienyl group, 6-pentafluoroethyl-3-methyl-2-benzothienyl group, 7-pentafluoroethyl-3methyl-2-benzothienyl group, 4-methoxy-3-methyl-2-benzothienyl group, 5-methoxy-3-methyl-2-benzothienyl group, 6-methoxy-3-methyl-2-benzothienyl group, group 7 -methoxy-3-methyl-2-benzothienyl, 4-trifluoromethoxy-3-methyl-2-benzothienyl group, 5-trifluoromethoxy-3methyl-2-benzothienyl group, 6-trifluoromethoxy-3-methyl-2-benzothienyl group, 7trifluoromethoxy-3 group -methyl-2-benzothienyl, 4-isopropyl-2-benzothienyl group, 5isopropyl-3-methyl-2-benzothienyl group, group 6-isopropyl-2-benzothienyl, group 7-isopropyl-2

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264/854 benzothienyl, 4-hexyl-2-benzothienyl group, 5-hexyl-2-benzothienyl group, 6-hexyl-

2-benzothienyl, 7-hexyl-2-benzothienyl group, 4-ethoxy-2-benzothienyl group, 5-ethoxy-2-benzothienyl group, 6-ethoxy-2-benzothienyl group, 7-ethoxy-2-benzothienyl group, group

4-fluoro-5-trifluoromethyl-2-benzothienyl, 6-fluoro-5-trifluoromethyl-2-benzothienyl group, 7-fluoro-5-trifluoromethyl-2-benzothienyl group, 4-chloro-5-trifluoromethyl-2benzothienyl group 6-chloro-5-tnfluoromethyl-2-benzothienyl, 7-chloro-5trifluoromethyl-2-benzothienyl group, 4-chloro-5-trifluoromethoxy-2-benzothienyl group, 6chloro-5-tnfluoromethoxy-2-benzothienyl group, group 7- chloro-5-trifluoromethoxy-2-benzothienyl, 4-fluoro-3-benzothienyl group, 5-fluoro-3-benzothienyl group, 6-fluoro-3benzothienyl group, 7-fluoro-3-benzothienyl group, 4-chloro-3 group -benzothienyl, 5chloro-3-benzothienyl group, 6-chloro-3-benzothienyl group, 7-chloro-3-benzothienyl group, 4-bromo-3-benzothienyl group, 5-bromo-3-benzothienyl group, 6-bromo group -3-benzothienyl, 7-bromo-3-benzothienyl group, 4-fluoro-3-benzothienyl group, 5-methyl-3benzothienyl group, 6-methyl-3-benzothienyl group, 7-methyl-3-benzothienyl group, group 4 trifluoromethyl-3-benzothienyl, group 5-trifluoromethyl-3-benzothienyl, group 6trifluoromet yl-3-benzothienyl, 7-trifluoromethyl-3-benzothienyl group, 4-fluoro-2methyl-3-benzothienyl group, 5-fluoro-2-methyl-3-benzothienyl group, 6-fluoro-2-methyl-3- group

benzothienyl, 7-fluoro-2-methyl-3-benzothienyl group, 4-chloro-2-methyl-3- group benzothienyl, 5-chloro-2-methyl-3-benzothienyl group, 6-chloro-2-methyl-3- group benzothienyl, 7-chloro-2-methyl-3-benzothienyl group, 4-bromo-2-methyl-3- group benzothienyl, 5-bromo-2-methyl-3-benzothienyl group, 6-bromo-2-methyl-3- group benzothienyl, 7-bromo-2-methyl-3-benzothienyl group, 4-fluoro-2-methyl-3- group benzothienyl, 5-methyl-2-methyl-3-benzothienyl group, 6-methyl-2-methyl-3- group benzothienyl, 7-methyl-2-methyl-3-benzothienyl group, 4-trifluoromethyl-2-methyl-3- group benzothienyl, 5-trifluoromethyl-2-methyl-3-benzothienyl group, 6-trifluoromethyl-2- group

methyl-3-benzothienyl, group 7-trifluoromethyl-2-methyl-3-benzothienyl, group 4-ethyl-3-

benzothienyl, 5-ethyl-3-benzothienyl group, 6-ethyl-3-benzothienyl group, 7-ethyl-3- group benzothienyl, 4-pentafluoroethyl-3-benzothienyl group, 5-pentafluoroethyl-3- group benzothienyl, 6-pentafluoroethyl-3-benzothienyl group, 7-pentafluoroethyl-3- group benzothienyl, 4-methoxy-3-benzothienyl group, 5-methoxy-3-benzothienyl group, group 6-

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265/854 methoxy-3-benzothienyl, 7-methoxy-3-benzothienyl group, 4-trifluoromethoxy-3benzothienyl group, 5-trifluoromethoxy-3-benzothienyl group, 6-trifluoromethoxy-3benzothienyl group, 7-trifluoromethoxy-3-benzothienyl group 4-isoprpyl-3-benzothienyl group, 5-isoprpyl-3-benzothienyl group, 6-isoprpyl-3-benzothienyl group, 7-isoprpyl-3benzothienyl group, 4-hexyl-3-benzothienyl group, 5-hexyl-3- group benzothienyl, 6-hexyl-

3-benzothienyl, 7-hexyl-3-benzothienyl group, 4-ethoxy-3-benzothienyl group, 5-ethoxy-3-benzothienyl group, 6-ethoxy-3-benzothienyl group, 7-ethoxy-3-benzothienyl group, group

4-fluoro-5-trifluoromethyl-3-benzothienyl, 6-fluoro-5-trifluoromethyl-3-benzothienyl group, 7-fluoro-5-trifluoromethyl-3-benzothienyl, 4-chloro-5-trifluoromethyl-3benzothienyl group 6-chloro-5-tnfluoromethyl-3-benzothienyl, 7-chloro-5trifluoromethyl-3-benzothienyl group, 4-chloro-5-trifluoromethoxy-3-benzothienyl group, 6chloro-5-tnfluoromethoxy-3-benzothienyl group, group 7- chloro-5-trifluoromethoxy-3-benzothienyl or the like.

[0346] A pyridyl group (which can be substituted on the pyridine ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen, phenyl group (which can be substituted in the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), furyl group and thienyl group ) includes a pyridyl group (which can be substituted on the pyridine ring by 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen, phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C 1 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), furyl group and thienyl group), for example, an unsubstituted 2pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-fluoro-2-pyridyl group, group 4 -fluoro-2-pyridyl, 5-fluoro-2-pyridyl group, 6-fluoro-2-pyridyl group, 3-chloro-2pyridyl group, 4-chloro-2-pyridyl group, 5-chloro-2-pyridyl group, group 6-chloro-2-pyridyl, group

6-chloro-4-methyl-2-pyridyl, 3,4,5-trichloro-2-pindyl group, 3-methyl-2-pyridyl group, group

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266/854

4-methyl-2-pyridyl, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 3-ethyl-2-pyridyl group, 4-ethyl-2-pyridyl group, 5-ethyl-2 group -pyridyl, 6-ethyl-2-pyridyl group, 3-n-propyl-2pyridyl group, 4-n-propyl-2-pyridyl group, 5-n-propyl-2-pyridyl group, 6-n-propyl- 2pyridyl, 5-ter-butyl-2-pyridyl group, 4-n-pentyl-2-pyridyl group, 5-n-hexyl-2-pyridyl group, 6-n-hexyl-2-pyridyl group, 2-chlorine group -3-pyridyl, group 4-chloro-3-pyridyl, group 5chloro-3-pyridyl, group 6-chloro-3-pyridyl, group 3-pyridyl, group 4-pyridyl, group 3-methyl-

3-pyridyl, 4-methyl-3-pyridyl group, 5-methyl-3-pyridyl group, 6-methyl-3-pyridyl group, 2-ethyl-3-pyridyl group, 4-ethyl-3-pyridyl group, group 5-ethyl-3-pyridyl, 6-ethyl-3pyridyl group, 2-propyl-3-pyridyl group, 4-propyl-3-pyridyl group, 5-propyl-3-pyridyl group, 6-propyl-3-pyridyl group , 5-ter-butyl-3-pyridyl group, 4-pentyl-3-pyridyl group, 5hexyl-3-pyridyl group, 6-hexyl-3-pyridyl group, 3-chloro-4-pyridyl group, 2-chlorine group -4-pyridyl, 3-methyl-4-pyridyl group, 2-methyl-4-pyridyl group, 3-trifluoromethyl-4-pyridyl group, 3-ethyl-4-pyridyl group, 2-ethyl-4-pyridyl group, 3-propyl-4-pyridyl group, 6-n-propyl-4pyridyl group, 5-ter-butyl-4-pyridyl group, 2-n-hexyl-4-pyridyl group, 3-phenyl-2-pyridyl group, group 4-phenyl-2-pyridyl, 5-phenyl-2-pyridyl group, 6-phenyl-2-pyridyl group, 2-phenyl-3pyridyl group, 2-phenyl-4-pyridyl group, 2-phenyl-5-pyridyl group , group 3- (4-fluorophenyl) -2-pyridyl, group 3- (3-fluoro-4-chlorophenyl) -2-pyridyl, group 3- (3-fluorophenyl) -2-pyridyl la, group 3- (4bromophenyl) -4-pyridyl, group 3- (3-fluorophenyl) -4-pyridyl, group 4- (2,3,4,5,6pentafluorophenyl) -2-pyridyl, group 4- (3 -fluoro-4-chlorophenyl) -2-pyridyl, group 4- (3-fluorophenyl) -2-pyridyl, group 3- (4-chlorophenyl) -2-pyridyl, group 4- (4-chlorophenyl) -2-pyridyl, group 5- (4-chlorophenyl) -2-pyridyl, group 6- (2,4,6-trichlorophenyl) -2-pyridyl, group 2- (4chlorophenyl) -3-pyridyl, group 2- (4-chlorophenyl) -4 -pyridyl, group 6- (4-chlorophenyl) -3-pyridyl, group 4- (3-fluoro-4-chlorophenyl) -2-pyridyl, group 5- (4-iodo-3-chlorophenyl) -2-pyridyl, group

6- (4-fluoro-3-chlorophenyl) -2-pyridyl, group 2- (4-fluoro-3-chlorophenyl) -3-pyridyl, group 2- (4-fluoro-3-chlorophenyl) -4-pyridyl, group 6- (4-fluoro-3-chlorophenyl) -3-pyridyl, group 5- (4trifluoromethylphenyl) -2-pyridyl, group 6- (4-trifluoromethylphenyl) -2-pyridyl, group 2- (4trifluoromethylphenyl) -3- pyridyl, trifluoromethylphenyl) -3-pyridyl, group 2- (4-trifluoromethylphenyl) -4-pyridyl, group 6- (4 group 5- (4-methylphenyl) -2-pyridyl, group 6- (4-methylphenyl) -2 pyridyl, group 2- (4-methylphenyl) -3-pyridyl, group 2- (4-methylphenyl) -4-pyridyl, group 6- (4 methylphenyl) -3-pyridyl, group 4-fluoro-2- (4- methoxyphenyl) -3-pyridyl, group 4-methyl-5-phenyl-3 Petition 870190039560, of 26/04/2019, page 275/876

267/854 chloro-2-pyridyl, group 5- (4-methoxyphenyl) -2-pyridyl, group 6- (4-methoxyphenyl) -2-pyridyl, group 2- (4-methoxyphenyl) -3-pyridyl, group 2 - (4-methoxyphenyl) -4-pyridyl, group 6- (4methoxyphenyl) -3-pyridyl, group 5- (4-trifluoromethoxyphenyl) -2-pindyl, group 6- (4trifluoromethoxyphenyl) -2-pyridyl, group 2- ( 4-trifluoromethoxyphenyl) -3-pyridyl, group 2- (4trifluoromethoxyphenyl) -4-pyridyl, group 6- (4-trifluoromethoxyphenyl) -3-pyridyl, group 5- (3chloro-4-trifluoromethoxyphenyl) -2-pyridyl, group 6 - (3-chloro-4-trifluoromethoxyphenyl) -2-pyridyl, group 2- (3-chloro-4-trifluoromethoxyphenyl) -3-pindyl, group 2- (3-chloro-4trifluoromethoxyphenyl) -4-pyridyl, group 6- (3-chloro-4-trifluoromethoxyphenyl) -3-pindyl, group

5- (3-fluoro-4-trifluoromethoxyphenyl) -2-pindyl, group 6- (3-fluoro-4-trifluoromethoxyphenyl) -2pyridyl, group 2- (3-fluoro-4-trifluoromethoxyphenyl) -3-pindyl, group 2 - (3-fluoro-4trifluoromethoxyphenyl) -4-pyridyl, group 6- (3-fluoro-4-trifluoromethoxyphenyl) -3-pindyl, group

5- (3,4-dimethoxyphenyl) -2-pyridyl, group 6- (3,4-dimethoxyphenyl) -2-pyridyl, group 2- (3,4dimethoxyphenyl) -3-pyridyl, group 2- (3,4- dimethoxyphenyl) -4-pyridyl, group 6- (3,4-dimethoxyphenyl) -3-pyridyl, group 5- (3,4-difluorophenyl) -2-pyridyl, group 6- (3,4-difluorophenyl) -

2-pyridyl, group 2- (3,4-difluorophenyl) -3-pyridyl, group 2- (3,4-difluorophenyl) -4-pyridyl, group 6- (3,4-difluorophenyl) -3-pyridyl, group 5- (3,4-dichlorophenyl) -2-pyridyl, group 6- (3,4dichlorophenyl) -2-pyridyl, group 2- (3,4-dichlorophenyl) -3-pyridyl, group 2- (3,4- dichlorophenyl) -4pyridyl, group 6- (3,4-dichlorophenyl) -3-pyridyl, group 5- (2-furyl) -2-pyridyl, group 6- (2-furyl) -

2-pyridyl, group 5- (2-furyl) -3-pyridyl, group 6- (2-furyl) -3-pyridyl, group 5- (3-furyl) -2pyridyl, group 6- (3-furyl) - 2-pyridyl, group 5- (3-furyl) -3-pyridyl, group 6- (3-furyl) -3-pyridyl, group 5- (2-thienyl) -2-pyridyl, group 6- (2-thienyl ) -2-pyridyl, group 5- (2-thienyl) -3-pyridyl, group 6- (2-thienyl) -3-pyridyl, group 5- (3-thienyl) -2-pyridyl, group 6- (3 -thienyl) -2-pyridyl, group 5- (3-thienyl) -3-pyridyl, group 6- (3-thienyl) -3-pyridyl or the like.

[0347] A furyl group (which can be substituted on the furan ring by 1 to 3 groups selected from a group consisting of a C1-8 alkyl group, nitro group and phenyl group (which can be substituted on the phenyl ring by at least a group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen and a nitro group)) includes a furyl group ( which can be replaced in the furan ring by 1 to 3 groups selected from a group consisting of

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268/854 of a C1-6 alkyl group, nitro group and phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen and a nitro group)), for example, a 2-furyl, 3-furyl group, 3-methyl-2-furyl group , 3,4-dimethyl-2-furyl group, 3,4,5-trimethyl-2-furyl group, 4-methyl-2-furyl group, 5-methyl-2-furyl group, 3-ethyl-2- group furyl, 4-ethyl-2-furyl group, 5-ethyl-2-furyl group, 3-n-propyl-2-furyl group, 4-n-propyl-2-furyl group, 5-n-propyl-2 group -furyl, group 3-n-butyl-2-furyl, group 4-n-butyl-2-furyl, group 5-n-butyl-2-furyl, group 3-n-pentyl-2-furyl, group 4-n- pentyl-2-furyl, group 5-n-pentyl-2-furyl, group 3-n-hexyl-2-furyl, group 4-nhexyl-2-furyl, group 5-n-hexyl-2-furyl, group 2 -methyl-3-furyl, 4-methyl-3-furyl group, 5-methyl-3-f group uryl, 2-ethyl-3-furyl group, 4-ethyl-3-furyl group, 5-ethyl-3-furyl group, 2-n-propyl-3-furyl group, 4-n-propyl-3-furyl group , 5-n-propyl-3-furyl group, 2-n-butyl-3-furyl group, 4-n-butyl-3-furyl group, 5-n-butyl-3-furyl group, 2-n-pentyl group 3-furyl, 4-n-pentyl-3-furyl group, 5-n-pentyl-3-furyl group, 2-n-hexyl-3-furyl group, 4-nhexyl-3-furyl group, 5-n group -hexyl-3-furyl, group 3-nitro-2-furyl, group 4-nitro-2-furyl, group 5-nitro-2-furyl, group 2-nitro-3-furiIa, group 4-nitro-3- furyl, 3-phenyl-2-furyl group, 4-phenyl-2-furyl group, 5-phenyl-2-furyl group, 3-phenyl-4-furyl group, 4-phenyl-3-furyl group, group 3- (3-fluorophenyl) -2-furiIa, group 4- (3-fluorophenyl) -2-furiIa, group 5- (3-fluorophenyl) -2furyl, group 2- (3-fluorophenyl) -3-furyl, group 3- (2-fluorophenyl) -2-furyl, group 4- (2-fluorophenyl) -2-furyl, group 5- (2-fluorophenyl) -2-furyl, group 2- (2-fluorophenyl) -3-furyl, group 4- nitro-3-furyl, group 3- (4-fluorophenyl) -2-furyl, group 4- (4-fluorophenyl) -2-furyl, group 5- (4-fluorophenyl) -2-furiIa, group 2- (4-fluorophenyl) -3-furiIa, group 4- (4-fluorophenyl) -3furyl, group 3- (3,4-difluorophenyl) -2-furyl , group 4- (2,3,4,5,6-pentafluorophenyl) -2-furyl, group 5- (3,4-difluorophenyl) -2-furyl, group 2- (3,4-difluorophenyl) -3- furyl, group 4- (3,4difluorophenyl) -3-furyl, group 3- (4-chlorophenyl) -2-furyl, group 4- (4-chlorophenyl) -2-furyl, group 5- (4-chlorophenyl) - 2-furyl, group 2- (4-chlorophenyl) -3-furyl, group 4- (4-chlorophenyl) -3furyl, group 3- (2-chlorophenyl) -2-furyl, group 4- (2-chlorophenyl) - 2-furyl, group 5- (2-chlorophenyl) -2-furyl, group 2- (2-chlorophenyl) -3-furyl, group 4- (2-chlorophenyl) -3-furyl, group 5- (2-chlorophenyl) - 3-furyl, group 3- (3-chlorophenyl) -2-furyl, group 4- (3-chlorophenyl) -2-furyl,

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269/854 group 5- (3-chlorophenyl) -2-furyl, group 2- (3-chlorophenyl) -3-furyl, group 4- (3-chlorophenyl) -3furyl, group 3- (3,4,5- trichlorophenyl) -2-furyl, group 4- (3,4-dichlorophenyl) -2-furyl, group 5 (3,4-dichlorophenyl) -2-furyl, group 2- (3,4-chlorophenyl) -3-furyl , group 4- (3,4-dichlorophenyl) -3 furyl, group 3- (4-methylphenyl) -2-furyl, group 4- (4-methylphenyl) -2-furyl, group 5- (4 methylphenyl) -2 -furyl, group 2- (4-methylphenyl) -3-furyl, group 4- (4-methylphenyl) -3-furyl, group

3- (4-trifluoromethylphenyl) -2-furyl, group 4- (4-trifluoromethylphenyl) -2-furyl, group 5- (4 trifluoromethylphenyl) -2-furyl, group 2- (4-trifluoromethylphenyl) -3-furyl, group 4- (4trifluoromethylphenyl) -3-furyl, group 3- (2-trifluoromethylphenyl) -2-furyl, group 4- (2trifluoromethylphenyl) -2-furyl, group 5- (2-trifluoromethylphenyl) -2-furyl, group 2 - (2trifluoromethylphenyl) -3-furyl, group 4- (2-trifluoromethylphenyl) -3-furyl, group 3- (3trifluoromethylphenyl) -2-furyl, group 4- (3-trifluoromethylphenyl) -2-furyl, group 5- ( 4trifluoromethylphenyl) -2-furyl, group 2- (3-trifluoromethylphenyl) -3-furyl, group 4- (3trifluoromethylphenyl) -3-furyl, group 3- (2-chloro-5-trifluoromethylphenyl) -2-funla, group

4- (2-chloro-5-trifluoromethylphenyl) -2-furyl, group 5- (2-chloro-5-trifluoromethylphenyl) -2-furyl, group

2- (2-chloro-5-trifluoromethylphenyl) -3-funnel, group 4- (2-chloro-5-trifluoromethylphenyl) -3-funnel, group 3- (4-methoxyphenyl) -2-furyl, group 4- ( 4-methoxyphenyl) -2-furyl, group 5- (4methoxyphenyl) -2-furyl, group 3- (4-methoxyphenyl) -4-furyl, group 4- (4-methoxyphenyl) -3-furyl, group 3- ( 2-methoxyphenyl) -2-furyl, group 4- (2-methoxyphenyl) -2-furyl, group 5- (2 methoxyphenyl) -2-furyl, group 2- (2-methoxyphenyl) -3-furyl, group 4- (2-methoxyphenyl) -3-furyl, group 3- (2-trifluoromethoxyphenyl) -2-funnel, group 4- (2-trifluoromethoxyphenyl) -2-funnel, group 5- (2-trifluoromethoxyphenyl) -2-funnel, group 3- (4-trifluoromethoxyphenyl) -2-funla, group 4- (4trifluoromethoxyphenyl) -2-funla, group 5- (4-trifluoromethoxyphenyl) -2-funla, group 2- (4 trifluoromethoxyphenyl) -3-funla, group 4 - (4-trifluoromethoxyphenyl) -3-funnel, group 3- (3,4-dimethoxyphenyl) -2-furyl, group 4- (3,4-dimethoxyphenyl) -2-furyl, group 5- (3,4-dimethoxyphenyl) -

2- furyl, group 3- (3,4-dimethoxyphenyl) -3-furyl, group 4- (3,4-dimethoxyphenyl) -3-furyl, group

3- (4-nitrophenyl) -2-furyl, group 4- (4-nitrophenyl) -2-furyl, group 5- (4-nitrophenyl) -2-furyl, group 2- (4-nitrophenyl) -3-furyl , group 4- (4-nitrophenyl) -3-furyl, group 3- (3-nitrophenyl) -2furyl, group 4- (3-n itrophenyl) -2-furyl, group 5- (3-n itrophenyl) l) -2-furyl, group 2- (3-nitrophenyl) 3-furyl, group 4- (3-nitrophenyl) -3-furyl, group 4-methyl-5-nitro-2-furyl, group 4- phenyl-3,5dimethyl-2-furyl or the like.

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270/854 [0348] A benzothiazole group (which may have at least one phenyl group on the benzothiazole ring which may have a C1-6 alkoxy group as a substituent on the phenyl ring) includes a benzothiazole group (which may have a benzothiazole ring of 1 to 3 phenyl groups which may have 1 to 3 C 1-6 alkoxy groups as a substituent on the phenyl ring), for example, a benzothiazol-2-yl group, benzothiazol-4-yl group, benzothiazol-5-yl group, benzothiazole-6-yl, benzothiazole-

7-yl, 2-phenylbenzothiazol-4-yl group, 2,5-diphenylbenzothiazol-4-yl group, 4,5,6-triphenylbenzothiazol-2-yl group, 2-phenylbenzothiazol-5-yl group, 2-phenylbenzothiazol-6 group -yl, 2-phenylbenzothiazol-7-yl group, 2- (3-ethoxyphenyl) benzothiazol-7-yl group, 2- (4propoxyphenyl) benzothiazol-4-yl group, 2- (4-n-butoxyphenyl) benzothiazole- group 5-yl, group 2- (4-nhexyloxyphenyl) benzothiazol-6-yl, group 2- (4-n-pentyloxyphenyl) benzothiazol-7-yl, group 4-phenylbenzothiazol-2-yl, group 5-phenylbenzothiazol-2-yl, group 6-phenylbenzothiazol-2-yl, group 7-phenylbenzothiazol-2-yl, group 4- (3,4-dimethoxyphenyl) benzothiazol-2-yl, group 5 (3,4,5-trimethoxyphenyl) benzothiazol-2-yl , group 7- (3-methoxyphenyl) benzothiazol-2-yl, group

4- (4-methoxyphenyl) benzothiazol-2-yl, group 5- (4-methoxyphenyl) benzothiazol-2-yl, group 6- (4methoxyphenyl) benzothiazol-2-yl, group 7- (4-methoxyphenyl) benzothiazol-2 -ila or similar.

[0349] A thienyl group (which may have at least one group on the thiophene ring selected from a group consisting of a halogen atom, nitro group, C1-8 alkyl group, pyrazolyl group that can be substituted on the pyrazole ring by at least a C1-6 alkyl group unsubstituted or substituted by halogen as a substituent and thienyl group that may have a halogen atom in the thiophene ring) includes a thienyl group (which may have 1 to 3 groups in the thiophene ring selected from a group that consists of a halogen atom, nitro group, C1-6 alkyl group, pyrazolyl group that can be substituted on the pyrazole ring by 1 to 3 unsubstituted C1-6 alkyl groups or substituted by halogen as a substituent and thienyl group that may have 1 to 3 halogen atoms in the thiophene ring), for example, a 2-thienyl, 3-fluoro-2-thienyl group, 4-fluoro-2-thienyl group, 5fluoro-2-thienyl group, 3-chloro- 2-thienyl, 4-chloro-2-thienyl group, g 5-chloro-2-thienyl group, 3-bromo-2-thienyl group, 4-bromo-2-thienyl group, 5-bromo-2-thienyl group, 3-thienyl group, 2-fluoro-3-thienyl group, group 4 -fluoro-3-thienyl, group 5-fluoro-3-thienyl, group

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271/854

2-chloro-3-thienyl, 4-chloro-3-thienyl group, 5-chloro-3-thienyl group, 2-bromo-3-thienyl group, 4-bromo-3-thienyl group, 5-bromo-3-thienyl group , group 3-nitro-2-thienyl, group

4- nitro-2-thienyl, 5-nitro-2-thienyl group, 2-nitro-3-thienyl group, 4-nitro-3-thienyl group, 5-nitro-3-thienyl group, 3-methyl-2 group -thienyl, 4-methyl-2-thienyl group, 5-methyl-2-thienyl group, 5-ethyl-2-thienyl group, 2-methyl-3-thienyl group, 4-methyl-3-thienyl group, 5methyl-3 group -thienyl, 2,5-dimethyl-3-thienyl group, 2,4,5-trimethyl-3-thienyl group, 2,4dimethyl-3-thienyl group, 3- (pyrazol-1-yl) -2-thienyl group , group 4- (pyrazol-1-yl) -2-thienyl, group 5 (pyrazol-1-yl) -2-thienyl, group 2- (pyrazol-1-yl) -3-thienyl, group 4- (pyrazole -1 -yl) -3-thienyl, group 5- (pyrazol-1-yl) -3-thienyl, group 3- (3-trifluoromethylpyrazol-1-yl) -2-thienyl, group 4- (3tnfluoromethylpyrazole-1 - iI) -2-thienyl, group 5- (1-methyl-3-trifluoromethylpyrazol-5-yl) -2-thienyl, group 2- (1,4,5-trimethylpyrazol-3-yl) -3-thienyl, group 4- (1,5-dimethylpyrazol-3-yl) -3-thienyl, group 5- (1-methyl-pyrazol-3-yl) -3-thienyl, group 5- (1 -n-pentyl-pyrazol-5 -il) -2-thienyl, group

5- (1-n-hexyl-pyrazol-5-yl) -2-thienyl, group 3- (5-trifluoromethylpyrazol-1-yl) -2-thienyl, group

4- (5-n-propyl-pyrazol-1-yl) -2-thienyl, group 5- (5-n-butyl-pyrazol-1-yl) -2-thienyl, group 2- (5trifluoromethylpyrazol-1-yl ) -3-thienyl, group 4- (5-ethyl-pyrazol-1-yl) -3-thienyl, group 5- (5-fluoromethylpyrazol-1-i) -3-thienyl, group 3- (2-thienyl) -2 -thienyl, group 4- (2-thienyl) -2-thienyl, group 3-chloro-4- (2-thienyl) -2-thienyl, group 5- (2-thienyl) -2-thienyl, group 2- ( 2-thienyl) -3 thienyl, group 4- (2-thienyl) -3-thienyl, group 5- (2-thienyl) -3-thienyl, group 3- (5-chloro-2-thienyl) 2-thienyl, group 4- (5-bromo-2-thienyl) -2-thienyl, group 5- (5-chloro-2-thienyl) -2-thienyl, group 2- (5-chloro-2-thienyl) -3-thienyl, group 4- (5-chloro-2-thienyl) -3-thienyl, group 5- (5-chloro-2-thienyl) -3-thienyl, group 3- (4-chloro-2-thienyl) -2-thienyl, group 4- (3,4-dichloro-2-thienyl) -2thienyl, group 5- (3,4,5-trichloro-2-thienyl) -2-thienyl, group 2- (4-bromo-2-thienyl) - 3-thienyl, group 4- (4-chloro-2-thienyl) -3-thienyl, group 5- (4-bromo-2-thienyl) -3-thienyl or the like. [0350] An indolyl group (which can be substituted on the indole ring by at least one group selected from a group consisting of a phenylsulfonyl group which can have a C1-6 alkyl group as a substituent, C1-6 phenyl alkyl group, group C1-6 alkoxycarbonyl and phenyl group) includes an indolyl group (which can be substituted on the indole ring by 1 to 3 groups selected from a group consisting of a phenylsulfonyl group which can have 1 to 3 C1-6 alkyl groups as a substituent, C1-6 alkyl phenyl group, C1-6 alkoxycarbonyl group and phenyl group), for example, a

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272/854 indole-1-yl, indole-2-yl, indole-3-yl, indole-4-yl, indole-5-yl, indole-6-yl, indole-7-yl, group 1 (benzenesulfonyl) indol-3-yl, group 1- (4-methylbenzenesulfonyl) indol-3-yl, group 1 (3,4-dimethylbenzenesulfonyl) indol-3-yl, group 1 - (3,4,6-trimethylbenzenesulfonyl) indole-

3-yl, group 1-benzylindol-3-yl, group 1- (2-phenethyl) indol-3-yl, group 1 - (1-phenethyl) indole-3yl, group 1- (3-phenylpropyl) indole-3 -yl, group 1- (4-phenylbutyl) indole-3-yl, group 1- (5-phenylpentyl) indol-3-yl, group 1- (6-phenylexyl) indol-3-yl, group 6-methoxycarbonylindol-3- ila, 6-ethoxycarbonylindol-3-yl group, 6-n-propoxycarbonylindol-3-yl group, 6-nbutoxycarbonylindol-3-yl group, 6-n-pentyloxycarbonylindol-3-yl group, 6-nhexyloxycarbonylindol-3-yl group , 2-phenylindol-3-yl group, 1-benzyl-6-phenyl-6methoxycarbonylindol-3-yl group, 1-benzyl-6-methoxycarbonylindol-3-yl group, 2-phenyl-1 (4-methylbenzenesulfonyl) indole group -3-line or similar.

[0351] A pyrrolyl group (which can be substituted on the pyrrole ring by at least one group selected from a group consisting of a phenyl group which can be substituted by at least one C1-6 alkyl group unsubstituted or substituted by halogen and group C1-6 alkyl) includes a pyrrolyl group (which can be substituted on the pyrrole ring by 1 to 3 groups selected from a group consisting of a phenyl group which can be substituted by 1 to 3 unsubstituted C1-6 alkyl groups or substituted by halogen and C1-6 alkyl group), for example, a 2-pyrrolyl group, 1-methyl-2-pyrrolyl group, 1-ethyl-2-pyrrolyl group, 1-n-propyl-2-pyrrolyl group, group 1-nbutil-2-pyrrolyl, group 1 -n-pentyl-2-pyrrolyl, group 1 -n-hexyl-2-pyrrolyl, group 3-pyrrolyl, group 1-methyl-3-pyrrolyl, group 1-ethyl-3 -pyrrolyl, group 1 -n-propyl-3-pyrrolyl, group 1-n-butyl-3-pyrrolyl, group 1 -n-pentyl-3-pyrrolyl, group 1 -n-hexyl-3-pyrrolyl, group 2,5dimethyl- 3-pyrrolyl, group 1 - (3-methylphenyl) -2,5-dimethyl-3-pyrrolyl, group 1- (4-methylphenyl) -

2,5-dimethyl-3-pyrrolyl, group 1 - (3-trifluoromethylphenyl) -2,5-dimethyl-3-pyrrolyl, group 1- (4trifluoromethylphenyl) -2,5-dimethyl-3-pyrrolyl, group 1 - ( 2,3-dimethylphenyl) -3-pyrrolyl, group 1 (4-methylphenyl) -3-pyrrolyl, group 1 - (3-trifluoromethylphenyl) -3-pyrrolyl, group 1- (4trifluoromethylphenyl) -3-pyrrolyl, group 1 - (3-methylphenyl) -3,5-dimethyl-2-pyrrolyl, group 1- (4m ethylphenyl) -3,5-dimethyl l-2-pyrrolyl, group 1 - (3-trifluoromethylphenyl) -3, 5-dim ethyl-2-pyrrolyl, group 1 - (4-trifluoromethylphenyl) -3,5-dimethyl-2-pyrrolyl, group 1 - (3-methylphenyl) -2-pyrrolyl, group 1 - (2,4, 6-trimethylphenyl) -2-pyrrolyl, group 1 - (3,5-ditrifluoromethylphenyl) -2-pyrrolyl,

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273/854 group 1 - (4-trifluoromethylphenyl) -2-pyrrolyl or the like.

[0352] A coumarila group includes a 4-coumarila group, 5-coumarila group, 6-coumarila group, 7-coumarila group or 8-coumarila group.

[0353] Examples of a benzimidazolyl group (which can be substituted on the benzimidazole ring by at least one thienyl group as a substituent) include a 2-benzimidazolyl group, 4-benzimidazolyl group, 5-benzimidazolyl group, group 6-

benzimidazolyl, group 2- (2-thienyl) -4-benzimidazolyl, group 2- (2-thienyl) -5- benzimidazolyl, group 2- (2-thienyl) -6-benzimidazolyl, group 2- (2-thienyl) -7- benzimidazolyl, group 2- (3-thienyl) -4-benzimidazolyl, group 2- (3-thienyl) -5- benzimidazolyl, group 2- (3-thienyl) -6-benzimidazolyl, group 2- (3-thienyl) -7-

benzimidazolyl or the like.

[0354] An oxazolyl group (which can be substituted on the oxazole ring by at least one phenyl group, as a substituent, which can have a halogen atom) includes an oxazolyl group (which can be replaced on the oxazole ring by 1 to 2 phenyl groups, as a substituent, which may have 1 to 5 halogen atoms), for example, a 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 2-phenyl-4-oxazolyl group, group 2- (4-fluorophenyl) -4-oxazolyl, 2,4-di (4-chlorophenyl) group -

5-oxazolyl, group 2- (4-chlorophenyl) -4-oxazolyl, group 2- (4-bromophenyl) -4-oxazolyl, group 2- (4-iodophenyl) -4-oxazolyl, group 2- (4-fluorophenyl ) -5-oxazolyl, group 2- (4-chlorophenyl) -5-oxazolyl, group 2- (4-bromophenyl) -5-oxazolyl, group 2- (4-iodophenyl) -5oxazolyl, group 2- (4-fluorophenyl) - 4-oxazolyl, group 2- (3,4-chlorophenyl) -4-oxazolyl, group 2- (4-bromophenyl) -5-oxazolyl, group 2- (4-iodophenyl) -5-oxazolyl, group 2- (2 , 3,4,5,6 pentafluorophenyl) -4-oxazolyl, group 2- (2,4,6-trichlorophenyl) -4-oxazolyl, group 2- (4bromophenyl) -5-oxazolyl, group 2- (4-iodophenyl ) -5-oxazolyl or the like.

[0355] A thiazolyl group (which can be substituted on the thiazole ring by at least one phenyl group which can be substituted by at least one group selected from a group consisting of a halogen atom, nitro group and phenyl group) includes a group thiazolyl (which can be substituted on the thiazole ring by 1 to 2 phenyl groups which can be replaced by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, nitro group and phenyl group ), per

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274/854 example, a 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 2-phenyl-4 thiazolyl group, 2-phenyl-5-thiazolyl group, 2,4-diphenyl-5-thiazolyl group, group 2 , 5-diphenyl-4 thiazolyl, group 2- (4-chlorophenyl) -4-thiazolyl, group 2- (4-fluorophenyl) -5-thiazolyl, group 2 (2,3,4,5,6-pentafluorophenyl) -4 -thiazolyl, group 2- (4-bromophenyl) -4-thiazolyl, group 2- (3,4-dichlorophenyl) -4-thiazolyl, group 2- (3,4-dichlorophenyl) -5-thiazolyl, group 2- (3, 4-difluorophenyl) -

5-thiazolyl, group 2- (2,4,6-trichlorophenyl) -4-thiazolyl, group 2- (3-chloro-4-nitrophenyl) -4thiazolyl, group 2- (4-phenyl-3-bromophenyl) -4 -thiazolyl, group 2- (4-nitrophenyl) -4-thiazolyl, group 2- (4-nitrophenyl) -5-thiazolyl, group 2- (2,4,6-trinitrophenyl) -5-thiazolyl, group 2- ( 2,4dinitrophenyl) -4-thiazolyl, group 2- (4-biphenylyl) -4-thiazolyl, group 2- (4-biphenylyl) -5-thiazolyl, group 4- (4-biphenylyl) -2-thiazolyl, group 2 - (4-biphenylyl) -4-thiazolyl or the like.

[0356] Examples of a quinolyl group include 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group or 8-quinolyl group.

[0357] Examples of a 3,4-dihydrocarbostyryl group (which can be substituted on the 3,4-dihydrocarbostyryl ring by at least one group selected from a group consisting of a C1-8 alkoxy group, C1-8 alkyl group, and phenyl alkoxy group Ci-β) or carbostyryl group (which can be substituted on the carbostyryl ring by at least one group selected from a group consisting of a Ci-e alkoxy group, Ci-e alkyl group, and Ci-β alkoxy group ) include a 3,4-dihydrocarbostyryl group (which can be substituted on the 3,4-dihydrocarbostyryl ring by 1 to 3 groups selected from a group consisting of a C1-8 alkoxy group, C1-8 alkyl group, and phenyl group alkoxy Ci-β) or carbostyryl group (which can be substituted on the carbostyryl ring by 1 to 3 groups selected from a group consisting of a Ci-e alkoxy group, Ci-e alkyl group, and phenyl Ci-e alkoxy group) , for example, a 3,4-dihydrocarbostyryl-1-yl group, 3,4-dihydrocarbostyryl-3-yl group, 3,4-dihydrocarbostyryl-4 group -yl, 3,4-dihydrocarbostyryl-5-yl group, 3,4-dihydrocarbostyryl-6-yl group, 3,4-dihydrocarbostyryl-7-yl group, 3,4dihydrocarbostyryl-8-yl group, carbostyryl-1 - group ila, carbostyryl-3-yl group, carbostyryl-4yl group, carbostyryl-5-yl group, carbostyryl-6-yl group, carbostyryl-7-yl group, carbostyryl-8-yl group, 6-methoxy-3,4 group -diidrocarbostiril-5-ila, 7-methoxy-3,4-dihydrocarbostyryl-5-yl group, 8-methoxy-3,4-dihydrocarbostyryl-5-yl group, 8-methoxy-1-methyl groupPetition 870190039560, 04/26/04 2019, p. 283/876

275/854

3.4- dihydrocarbostyryl-5-yl, 8-benzyloxy-3,4-dihydrocarbostyryl-5-yl group, 8methoxycarbostyryl-5-yl group, 8-methoxy-1-methyl-carbostyryl-5-yl group, 8benzyloxycarbostiryl-5- group ila, 8-methoxy-3,4-dihydrocarbostyryl-6-yl group, 6-methyl-3,4 dihydrocarbostyryl-5-yl group, 6,7-dimethyl-3,4-dihydrocarbostyryl-5-yl group, group 1, 5,6-trimethyl-

3.4- dihydrocarbostyryl-7-yl, 6-methylcarbostyryl-5-yl group, 6,7-dimethylcarbostyryl-5yl group, 1,5,6-trimethylcarbostinl-7-yl group, 8-methoxy-1-methyl-3 group, 4-dihydrocarbostyryl-6yl, 8-benzyloxy-3,4-dihydrocarbostyryl-6-yl group, 8-methoxycarbostyryl-6-yl group, 8methoxy-1-methylcarbostyryl-6-yl group, 8-benzyloxy-carbostyryl-6- group ila, 8-methoxy-3,4-dihydrocarbostyryl-7-yl group, 8-methoxy-1-methyl-3,4-dihydrocarbostyryl-7-yl group, 8-benzyloxy-3,4-dihydrocarbostyryl-7-yl group, group 8- ethoxycarbostyryl-7-yl, 8-methoxy-1propyl-carbostyryl-7-yl group, 8- (2-phenylethoxy) carbostyryl-7-yl group or the like.

[0358] Examples of an imidazo [2,1-b] thiazolyl group include, as a 6imidazo [2,1-b] thiazolyl group, 5-imidazo [2,1-b] thiazolyl group, 3-imidazo group [2 , 1-b] thiazolyl and 2-imidazo [2,1-b] thiazolyl group or the like.

[0359] Examples of an imidazo [2,1-a] pyridyl group include a 2imidazo [2,1 -a] pyridyl group, 3-imidazo [2,1 -a] pyridyl group, 5-imidazo group [2,1 -a] pyridyl, group 6-imidazo [2,1 -a] pyridyl, group 7-imidazo [2,1 -a] pyridyl or the like.

[0360] A chromanyl group (which can be substituted on the Cromanian ring by at least one C 1 -alkyl group) includes a chromanyl group (which can be substituted on the Cromanian ring by 1 to 3 C 1 -alkyl groups), for example , a 2-methyl-5-chromanyl group, 2,2-dimethyl-5-chromanyl group, 2-methyl-6-chromanyl group, 2-ethyl-6-chromanyl group, 2-n-propyl-6-chromanyl group, group 2- n-butyl-6-chromanyl, group 2-n-pentyl-

6-chromanyl, 2-n-hexyl-6-chromanyl group, 2,2-dimethyl-6-chromanyl group, 2,2diethyl-6-chromanyl group, 2-methyl-7-chromanyl group, 2,2-dimethyl group -7-cromanila, group

2.2.4- trimethyl-6-chromanyl, 2-methyl-8-chromanyl group, 2,2-dimethyl-8-chromanyl group or the like.

[0361] Examples of a 2,3-dihydrobenzofuryl group include a 2,3-dihydro-

4-benzofuryl, 2,3-dihydro-5-benzofuryl group, 2,3-dihydro-6-benzofuryl group, 2,3-dihydro-7-benzofuryl group or the like.

[0362] A C1-6 alkyl group substituted by amino (which may have at least

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276/854 minus a group selected from a group consisting of a phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group halogen and C1-6 alkoxy group unsubstituted or substituted by halogen) and C1-6 alkyl group as a substituent) includes an amino substituted C1-6 alkyl group (which may have 1 to 2 groups selected from a group consisting of of a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and group C1-6 alkoxy unsubstituted or substituted by halogen) and C1-6 alkyl group as a substituent), for example, an aminomethyl group, 2-aminoethyl group, 1-aminoethyl group, 3aminopropyl group, 4-aminobutyl group, group 5- aminopentyl, 6-aminoexyl group, group

2- methyl-3-aminopropyl, 1,1-dimethyl-2-aminoethyl group, 2- (methylamino) ethyl group, 3- (methylamino) propyl group, 4- (methylamino) butyl group, 5- (methylamino) pentyl group , group 6- (methylamino) hexyl, dimethylaminomethyl group, group 2- (diethylamino) ethyl, group

3- (di-n-propylamino) propyl, group 4- (di-n-butylamino) butyl, group 5- (di-n-pentylamino) pentyl, group 2- (di-n-hexylamino) hexyl, group anilinomethyl, group 2 - (Nmethylanilino) ethyl, group 3- (N-methylanilino) propyl, group 4-anilinobutyl, group 2- (N methyl-4-chloroanilino) ethyl, group 3- (N-methyl-4-chloroanilino) propyl, group 4 - (N-methyl-4-chloroanilino) butyl, group 2- (N-methyl-4-fluoroanilino) ethyl, group 3- (N-methyl-2,3,4,5,6pentafluoroanilino) propyl, fluoroanilino) propyl, fluoroanilino) ethyl, fluoroanilino) butyl, chloroanilino) propyl, dichloroanilino) ethyl, chloroanilino) butyl, methylanilino) ethyl, group 2- (N-ethyl-3,5-ditrifluoromethylanilino) ethyl, group 2- (N-methyl-3,5ditrifluoromethylanilino) ethyl, group 2- (N-methyl-2,4-dimethylanilino) ethyl, group 2- (N-methyl-

3,5-dimethoxyanilino) ethyl, group 2- (2,4,6-trimethylanilino) ethyl, group 2- (3,4,5 group 2- (3-fluoroanilino) ethyl, group 4- (3-fluoroanilino) butyl , 3- (2-fluoro-anilino) propyl, 2- (N-methyl-2-chloroanilino) ethyl, 4- (N-methyl-2-chloroanilino) butyl, group group group group group group group group group

3- (N-methyl-3-

2- (N-methyl-2-

4- (N-methyl-2-

3- (N-methyl-2-

2- (N-methyl-2,3group group 3- (N-methyl-2,4,6-trichloroanilino) propyl, group 4- (N-methyl-3group 2- (N-methyl-4-thfluoromethylanilino) ethyl, group 2- (4Petition 870190039560, of 26/04/2019, page 285/876

277/854 trimethoxyanilino) ethyl, group 3- (N-methyl-4-trifluoromethylanilino) propyl, group 4- (Nmethyl-4-trifluoromethylanilino) butyl, group 2- (N-methyl-3-trifluoromethylanilino) ethyl, group 3 - (N-methyl-3-trifluoromethylanilino) propyl, group 2- (N-methyl-2-trifluoromethylanilino) ethyl, group 3- (N-methyl-2-trifluoromethylanilino) propyl, group 4- (N-methyl-2-trifluoromethylaniline) butyl, ethyl group 2- (N-methyl-4-trifluoromethoxyanilino), group 3- (Nmethyl-4-trifluoromethoxyanilino) propyl, group 4- (4-trifluoromethoxyanilino) butyl, group 2 (N-methyl-3-trifluoromethoxyanilino) ethyl , ethyl group 3- (N-methyl-3-trifluoromethoxyanilino), 4- (N-methy-3-trifluoromethoxyanilino) butyl group, ethyl group 2- (N-methyl-2-trifluoromethoxyanilino), group 3- (N-methyl-2 -trifluoromethoxyanilino) propyl, group 4 (N-methyl-2-trifluoromethoxyanilino) butyl, group 2- (N-methyl-4-methoxyanilino) ethyl, group 3 (N-methyl-4-methoxyanilino) propyl, group 4- (N -methyl-4-methoxyanilino) butyl, group 2- (Nmethyl-3-methoxyanilino) ethyl, group 3- (N-methyl-3-methoxy ianilino) propyl, group 4- (3-methoxyanilino) butyl, group 2- (2-methoxyanilino) ethyl, group 3- (N-methyl-2-methoxyanilino) propyl, group 4- (N-methyl-2-methoxyanilino) butyl or similar.

[0363] Examples of a 1,4-dioxaazaospiro [4,5] decyl group (which can be substituted on the 1,4-dioxa-azaespiro [4,5] decane ring by at least one oxo group as a substituent) include a 1,4-dioxa-8-azospiro group [4,5] dec-8-yl, 7oxo-1,4-dioxa-8-azospiro group [4,5] dec-8-yl, 6-oxo-1 group , 4-dioxa-8-aspasospiro [4,5] dec-

8-ila or similar.

[0364] A homopiperazinyl group (which can be substituted on the homopiperazine ring by at least one group selected from a group consisting of a C1-6 alkoxycarbonyl group, a C1-6 alkoxycarbonyl phenyl group and an unsubstituted or substituted phenyl group includes a homopiperazinyl group (which can be substituted on the homopiperazine ring by 1 to 3 groups selected from a group consisting of a C1-6 alkoxycarbonyl group, a C1-6 alkoxycarbonyl phenyl group and phenyl group unsubstituted or substituted by phenyl, for example , a 1homopiperazinyl group, 2-homopiperazinyl group, 3-homopiperazinyl group, 4homopiperazinyl group, 5-homopiperazinyl group, 6-homopiperazinyl group, 7homopiperazinyl group, 4-methoxycarbonyl-1-homopiperazinyl group, 4-etoxicaricar group

1-homopiperazinyl, group 4-n-propoxycarbonyl-1-homopiperazinyl, group 4-ter

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278/854 butoxycarboni 1-1 -homopiperazinyl, group 4-n-pentyloxycarbonyl-1 -homopiperazinyl, group 4-n-hexyloxycarbonyl-1-homopiperazinyl, group 4-benzyloxycarbonyl-1homopiperazinyl, group 4- (2-phenylethoxycarbonyl) homopiperazinyl, group 4- (3-phenylpropoxycarbonyl) -1 -homopiperazinyl, group 4- (4-phenylbutoxycarbonyl) -1 homopiperazinyl, group 4- (5-phenylpentyloxycarbonyl) -1-homopiperazinyl, group 4- (6-phenylexyloxycarbonyl) -1-group, homomiper 4- (4-biphenyl) -1-homopiperazinyl, 3,4-diphenyl-1-homopiperazinyl group, 3,4,5-triphenyl-1-homopiperazinyl group, 3-phenyl-4-methoxycarbonyl-1-homopiperazinyl group or similar.

[0365] A piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from a group consisting of an oxo group, C1-6 alkyl group and phenyl C1-6 alkyl group (which can be substituted on the phenyl ring) by at least one unsubstituted or substituted halogen C1-6 alkyl group)) includes a piperazinyl group (which can be substituted on the piperazine ring by 1 to 3 groups selected from a group consisting of an oxo group, C1- alkyl group 6 and phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 unsubstituted or substituted halogen C1-6 alkyl groups), for example, a piperazin-1 -yl group, piperazine-2 group -yl, piperazine-3-yl group, piperazine-4-yl group, 1-methyl-piperazine-4-yl group, 1-benzyl-piperazine-4-yl group, 1,2-dimethyl piperazine-4-yl group , oxopiperazine-4-yl, oxopiperazine-4-yl, oxopiperazine-4-yl, oxopiperazine-4-yl, dimethylbenzyl) piperazine-4-yl, (3,5-ditrif luoromethylbenzyl) piperazine-4-yl, group 1 - (4-methylbenzyl) -2-oxopiperazine-4yl, group 1- (4-trifluoromethylbenzyl) -2-oxopiperazine-4-yl, group 1- [2- (4group group group

1-benzyl-2,6-dimethyl-piperazine-4-yl, group 1-ethyl-21-n-propyl-2-oxopiperazine-4-yl,

1-n-butyl-2-oxopiperazine-4-yl,

1-n-pentyl-2-oxopiperazine-4-yl,

1- (4-benzyl) -2-oxopiperazine-4-yl, group 1- (2,4group 1 - (2,4,6-trimethylbenzyl) piperazine-4-yl, group 1group group group group group

-isopropyl-21 -ter-butyl-21-n-hexyl-2trifluoromethylphenyl) ethyl] -2-oxopiperazino-4-ia, group 1 - [3- (4-trifluoromethylphenyl) propyl] -2oxopiperazine-4-yl, group 1 - [4- (4-trifluoromethylphenyl) butyl] -2-oxopiperazine-4-yl, group 1 - [5- (4-trifluoromethylphenyl) pentyl] -2-oxopiperazine-4-yl, group 1 - [6- (4trifluoromethylphenyl) ) hexyl] -2-oxopiperazine-4-yl or the like.

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279/854 [0366] Examples of a piperidyl group (which can be substituted on the piperidine ring by at least one oxo group as a substituent) include a 1piperidyl group, 2-piperidyl group, 3-piperidyl group, 4-piperidyl group, group 2-oxo-1piperidyl, 3-oxo-1-piperidyl group, 4-oxo-1-piperidyl group or the like.

[0367] A pyrrolidine group (which can be substituted on the pyrrolidine ring by at least one C1-6 alkyl phenoxy group that may have an unsubstituted or halogen substituted C1-6 alkoxy group as a substituent) includes a pyrrolidinyl group (which may substituted on the pyrrolidine ring by 1 to 3 phenoxy C1-6 alkyl groups which may have 1 to 3 C1-6 alkoxy groups unsubstituted or substituted by halogen as a substituent), for example, a pyrrolidin-1-yl group, group pyrrolidin-2-yl, pyrrolidin-3-yl group, 2-phenoxymethylpyrrolidin-1-yl group, 3-phenoxymethylpyrrolidin-1-yl group, group 2- (2,4-dimethoxyphenoxymethyl) pyrrolidin-1-yl, group 2 ( 2,4,6-trimethoxyphenoxymethyl) pyrrolidin-1 -yl, 2,3-diphenoxymethylpyrrolidin-1 -yl, group

1,3,4-phenoxymethylpyrrolidin-2-yl, group 2- (4-methoxyphenoxymethyl) pyrrolidin-1-yl, group 2-

(4-trifluoromethoxyphenoxymethyl) pyrrolidin-1-yl, group 2- [2- (3- trifluoromethoxyphenoxy) ethyl] pyrrolidin-1-yl, group 2- [3- (4- trifluoromethoxyphenoxy) propyl] pyrrolidin-1-yl, group 2- [4- (4- trifluoromethoxyphenoxy) butyl] pyrrolidin-1-yl, group 2- [5- (4- trifluoromethoxyphenoxy) pentyl] pyrrolidin-1-yl, group 2- [6- (4-

trifluoromethoxyphenoxy) hexyl] pyrrolidin-1-yl, group 3- (4-methoxyphenoxymethyl) pyrrolidin-1-yl, group 3- (3-trifluoromethoxyphenoxymethyl) pyrrolidin-1-yl, group 3- (4trifluoromethoxyphenoximethyl) pyrrolidin similar.

[0368] Examples of an isoindolinyl group include a 2-isoindolinyl group, group 1-isindolinyl, group 3-isoindolinyl, group 4-isoindolinyl, group 5-isoindolinyl, group

6-isoindolinyl or similar.

[0369] Examples of an oxazolidinyl group (which can be substituted on the oxazolidine ring by at least one oxo group as a substituent) include a 2oxazolidinyl group, 3-oxazolidinyl group, 4-oxazolidinyl group, 5-oxazolidinyl group, group

2-oxo-3-oxazolidinyl or the like.

[0370] A benzo-1,3-oxazolidinyl group (which can be substituted in the benzo ringPetition 870190039560, of 26/04/2019, page 288/876

280/854

1.3- oxazolidine by at least one group selected from a group consisting of an oxo group, halogen atom and phenyl group as a substituent) includes a benzo-1,3-oxazolidinyl group (which can be substituted on the benzo-1 ring, 3-oxazolidine by 1 to 3 groups selected from a group consisting of an oxo group, halogen atoms and phenyl group as a substituent), for example, a benzo-1,3oxazolidin-2-yl group, benzo-1 group , 3-oxazolidin-3-yl, benzo-1,3-oxazolidin-4-yl group, benzo-1,3-oxazolidin-5-yl group, benzo-1,3-oxazolidin-6-yl group, benzo group -1,3oxazolidin-7-yl, group 2-oxobenzo-1,3-oxazolidin-3-yl, group 4-chloro-2-oxobenzo-

1.3- oxazolidin-3-yl, 5-chloro-2-oxobenzo-1,3-oxazolidin-3-yl group, 5-bromo-2oxobenzo-1,3-oxazolidin-3-yl group, 5-fluoro-benzo group -1,3-oxazolidin-3-yl, 6-phenyl-benzo-1,3-oxazolidin-3-yl group, 5-bromo-6-phenyl-2-oxobenzo-1,3-oxazolidin-3ila group, group 6- chloro-2-oxobenzo-1,3-oxazolidin-3-yl, group 7-chloro-2-oxobenzo-1,3oxazolidin-3-yl, group 5-bromo-2-oxobenzo-1,3-oxazolidin-3- ila, 4-phenyl-2oxobenzo-1,3-oxazolidin-3-yl group, 5-phenyl-2-oxobenzo-1,3-oxazolidin-3-yl group, 6phenyl-2-oxobenzo-1,3-oxazolidin group -3-yl, 7-phenyl-2-oxobenzo-1,3-oxazolidin-3-yl group or the like.

[0371] An imidazolidinyl group (which can be substituted on the imidazolidine ring by at least one group selected from a group consisting of an oxo group, phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by 1 to 3 groups) selected from a group consisting of a halogen atom and a C1-6 alkoxy group) and a phenyl group) includes an imidazolidinyl group (which can be substituted on the imidazolidine ring by 1 to 3 groups selected from a group consisting of an oxo group, C1-6 alkyl phenyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of a halogen atom and a C1-8 alkoxy group) and phenyl group), for example, an imidazolidin group -1 -yl, imidazolidin-2-yl group, imidazolidin-3-yl group, imidazolidin-4-yl group, imidazolidin5-yl group, 3-benzyl-imidazolidin-1-yl group, 3,4-dibenzyl-2 group -oxoimidazolidin-1-yl, group 2-oxoimidazolidin-1-yl, group 3-benzyl-2-oxoimidazolidin-1-yl a, group 3- (2-fluorobenzyl) -2-oxoimidazolidin-1-yl, group 3- (3-fluorobenzyl) -2-oxoimidazolidin-1-yl, group 3- (4-fluorobenzyl) -2-oxoimidazolidin-1-yl , 3-phenyl-2-oxoimidazolidin-1-yl group,

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281/854 group 3- (3,4-difluorobenzyl) -2-oxoimidazolidin-1-yl, group 3- (3,5-difluorobenzyl) -2oxoimidazolidin-1-yl, group 3- (3,4,5-trifluorobenzyl ) -2-oxoimidazolidin-1-yl, group 3 (2-chlorobenzyl) -2-oxoimidazolidin-1 -yl, group 3- (3-chlorobenzyl) -2-oxoimidazolidin-1 -yl, group 3- (4-chlorobenzyl ) -2-oxoimidazolidin-1-yl, group 3- (2,3-dichlorobenzyl) -2oxoimidazolidin-1-yl, group 3- (3,4-dichlorobenzyl) -2-oxoimidazolidin-1-yl, group 3- ( 3,5dichlorobenzyl) -2-oxoimidazolidin-1 -yl, group 3- (3,4,5-trichlorobenzyl) -2-oxoimidazolidin-

1-yl, group 3- (2-bromobenzyl) -2-oxoimidazolidin-1-yl, group 3- (3-bromobenzyl) -2oxoimidazolidin-1-yl, group 3- (4-bromobenzyl) -2-oxoimidazolidin-1 -yl, group 3- (2-methoxybenzyl) -2-oxoimidazolidin-1 -yl, group 3- (3-methoxybenzyl) -2-oxoimidazolidin-1 yl, group 3- (4-methoxybenzyl) -2-oxoimidazolidin-1-yl , group 3- (2,4-dimethoxybenzyl) -2oxoimidazolidin-1-yl, group 3- (2,4,6-trimethoxybenzyl) -2-oxoimidazolidin-1-yl, group 3 (3,5-dimethoxybenzyl) -2 -oxoimidazolidin-1-yl, group 3- (4-ethoxybenzyl) -2oxoimidazolidin-1-yl, group 3- (4-isopropoxybenzyl) -2-oxoimidazolidin-1-yl, group 3- (4n-butoxybenzyl) -2- oxoimidazolidin-1-yl, group 3- (4-n-pentyloxybenzyl) -2oxoimidazolidin-1-yl, group 3- (4-hexyloxybenzyl) -2-oxoimidazolidin-1-yl, group 3- [2- (3methoxy-4 -chlorophenyl) ethyl] -2-oxoimidazolidin-1-yl, group 3- [3- (4-chlorophenyl) propyl] -2oxoimidazolidin-1-yl, group 3- [4- (4-chlorophenyl) butyl] -2- oxoimidazolidin-1-yl, group 3- [5 (4-chlorophenyl) pentyl] -2-oxoimidazolidin-1-yl, group 3- [6- (4-chlorophenyl) hexyl] -2ox oimidazolidin-1-yl, 2-phenylidazolidin-1-yl group, 3-phenyl-2-benzylidazolidin-1-yl group, 3-phenyl-4-benzyl-2-oxoidazolidin-1-yl group, 3-phenyl-5 group -benzyl-2-oxoidazolidin-1-yl, 4-phenyl-2-oxoidazolidin-1-yl group or the like.

[0372] A benzimidazolidinyl group (which can be substituted on the benzimidazolidine ring by at least one group selected from a group consisting of an oxo group, halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen, amino group that can have a C1-6 alkyl group as a substituent, C1-6 alkoxycarbonyl group and, piperidyl group that can be substituted on the piperidine ring by at least one group selected from a group consisting of a C1-6 alkyl group, a phenyl group that can substituted on the phenyl ring by 1 to 3 halogen atoms, C1-6 alkoxycarbonyl group and a C1-6 phenyl alkoxycarbonyl group as a substituent) includes a benzimidazolidinyl group (which can be substituted

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282/854 on the benzimidazolidine ring by 1 to 3 groups selected from a group consisting of an oxo group, halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen, amino group which may have 1 to 2 alkyl groups C1-6 as a substituent, C1-6 alkoxycarbonyl group, and piperidyl group that can be substituted on the piperidine ring by 1 to 3 groups selected from a group consisting of a C1-8 alkyl group, a phenyl group that can be substituted on phenyl ring with 1 to 3 halogen atoms, C1-6 alkoxycarbonyl group and a C1-6 phenyl alkoxycarbonyl group as a substituent), for example, a benzimidazolidin-1-yl group, benzimidazolidin-2-yl group, benzimidazolidin- group 3-yl, benzimidazolidin-4-yl group, benzimidazolidin-5-yl group, benzimidazolidin-6-yl group, benzimidazolidin-7ila group, 2-oxobenzimidazolidin-1-yl group, 3-methyl-2-oxobenzimidazolidin-1- group ila, 3-methyl-benzimidazolidin-1-yl group, 6-dimethylaminobe group nzimidazolidin-1-yl, 6-ethoxycarbonylbenzimidazolidin-1-yl group, 3- (4-phenylpiperidin-4yl) benzimidazolidin-1-yl group, 4-fluoro-benzimidazolidin-1-yl group, 3-ethyl-2oxobenzimidazolidin-1 group -yl, 3-n-propyl-2-oxobenzimidazolidin-1-yl group, 3-n-butyl-2-oxobenzimidazolidin-1-yl group, 3-n-pentyl-2-oxobenzimidazolidin-1-yl group, group

3-n-hexyl-2-oxobenzimidazolidin-1-yl, 3-methyl-6-fluoro-2-oxobenzimidazolidin-1-yl group, 3-methyl-4-fluoro-2-oxobenzimidazolidin-1-yl group, group 3- methyl-5-fluoro-2oxobenzimidazolidin-1-yl, 3-methyl-7-fluoro-2-oxobenzimidazolidin-1-yl group, 3-methyl-6-chloro-2-oxobenzimidazolidin-1-yl group, 3-methyl group -5-chloro-2oxobenzimidazolidin-1-yl, 3-methyl-4-chloro-2-oxobenzimidazolidin-1-yl group, 3methyl-5-chloro-2-oxobenzimidazolidin-1-yl group, 3-methyl-7- group chloro-2-oxobenzimidazolidin-1-yl, 3-methyl-6-bromo-2-oxobenzimidazolidin-1-yl group, 3-methyl-4-bromo-2-oxobenzimidazolidin-1-yl group, 3-methyl-5 group -bromo-2oxobenzimidazolidin-1-yl, 3-methyl-7-bromo-2-oxobenzimidazolidin-1-yl group, 3-ethyl-6-fluoro-2-oxobenzimidazolidin-1-yl group, 3-isopropyl-6- group fluoro-2oxobenzimidazolidin-1-yl, 3-n-hexyl-6-fluoro-2-oxobenzimidazolidin-1-yl, 3-ethyl-6-chloro-2-oxobenzimidazolidin-1-yl group, 3-isopropyl-6 group -chloro-2oxobenzimidazolidin-1-yl, group 3-n-hexyl-6-chloro-2-o xobenzimidazolidin-1-yl, 3-ethyl-5-chloro-2-oxobenzimidazolidin-1-yl group, 3-isopropyl-5-chloro-2 group

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283/854 oxobenzimidazolidin-1-yl, 3-ter-butyl-5-chloro-2-oxobenzimidazolidin-1-yl group, 3-methyl-6-ethoxycarbonyl-2-oxobenzimidazolidin-1 -yl group, 3-isopropyl- group 6-ethoxycarbonyl-

2-oxobenzimidazolidin-1-yl, group 3-n-propyl-6-ethoxycarbonyl-2-oxobenzimidazolidin1 -yl, group 3-methyl-6-trifluoromethyl-2-oxobenzimidazolidin-1-yl, group 5-trifluoromethyl-

2-oxobenzimidazolidin-1-yl, 3-methyl-5-trifluoromethyl-2-oxobenzimidazolidin-1-yl group, 3-isopropyl-5-trifluoromethyl-2-oxobenzimidazolidin-1-yl group, group 3- (4-pheni Ipiperididium in-1 -yl) -2-oxobenzimidazolidin-1 -yl, group 3- (4-phenyl Ipiperid in-1 -yl) -5trifluoromethyl-2-oxobenzimidazolidin-1 -yl, group 3- (4-phenylpiperid in -1 -yl) -6trifluoromethyl-2-oxobenzimidazolidin-1 -yl, 3-methyl-6-dimethylamino-2oxobenzimidazolidin-1 -yl group, 3-ethyl-6-dimethylamino-2-oxobenzimidazolidin-1 -yl group 3 -methyl-6-amino-2-oxobenzimidazolidin-1-yl, group 3-isopropyl-6-dimethylamino-

2- oxobenzimidazolidin-1 -yl, oxobenzimidazolidin-1 -yl, oxobenzimidazolidin-1 -yl, oxobenzimidazolidin-1 -yl, oxobenzimidazolidin-1 -yl, oxobenzimidazolidin-1 -yl, oxobenzimidazolidin-1 -yl, oxobenzimidazole oxobenzimidazolidin-1 -ila, oxobenzimidazolidin-1 -ila, oxobenzimidazolidin-1 -ila, oxobenzimidazolidin-1 -ila, oxobenzimidazolidin-1 -ila,

3- (1-ter-butoxycarbonylpiperidin-4-yl) -2-oxobenzimidazolidin-1-yl, group group group group group

3- [4- (3-fluorophenyl) piperidin-1-yl] -23- [4- (4-fluorophenyl) piperidin-1-yl] -23- [4- (3-chlorophenyl) piperidin-1-yl] -23- [4- (4-chlorophenyl) piperidin-1-yl] -2group

3- [4- (2,3-difluorophenyl) piperidin-1-yl] -5-chloro-23- [4- (4-fluorophenyl) piperidin-1-yl] -5-chloro-2group 3- [4- (2,4,6-trichlorophenyl) piperid in-1 -yl] -5-chloro-23- [4- (4-chlorophenyl) piperidin-1-yl] -5-chloro-23- [4- (3 -fluorophenyl) piperidin-1-yl] -6-chloro-23- [4- (4-iodophenyl) piperidin-1-yl] -6-chloro-23- [4- (3-bromophenyl) piperidin-1-yl ] -6-chloro-23- [1-methylpiperidin-4-yl] -6-chloro-2group 3- (piperidin-4-yl) -2-oxobenzimidazolidin-1-yl, group 3group group group group group group (benzyloxycarbonylpiperidin -4-yl) -2-oxobenzimidazolidin-1 -yl, group 3- (piperidin-4-yl) -6 fluoro-2-oxobenzimidazolidin-1 -yl, group 3- (1-ter-butoxycarbonylpiperidin-4-yl) -6fluoro-2-oxobenzimidazolidin-1 -yl, group 3- (1-benzyloxycarbonylpiperidin-4-yl) -6-fluoro2-oxobenzimidazolidin-1 -yl, group 3- (piperidin-4-yl) -6-chlorine-2 -oxobenzimidazolidin-1-yl, group 3- (1-tert-butoxycarbonylpiperidin-4-yl) -6-chloro-2-oxobenzimidazolidin-1 -yl,

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284/854 group 3- (1-benzyloxycarbonyl-4-pipendin-4-yl) -6-chloro-2-oxobenzimidazolidin-1-yl, group 3- (1,2-dimethylpiperidin-4-yl) benzimidazolidin-1- ila, group 3- (1-benzyloxycarbonyl2-methylpiperidin-4-yl) benzimidazolidin-1-yl, group 3- (1,2,6-trim ethylpiperidin-4-i) benzimidazolidin-1-yl or the like.

[0373] A phthalimide group includes, for example, a phthalimid-2-yl group or the like. [0374] An indolinyl group (which can be substituted by at least one group selected from a group consisting of a C1-8 alkyl group, halogen atoms and oxo group as a substituent on the indoline ring) includes an indolinyl group (which can present from 1 to 3 groups selected from a group consisting of a C1-6 alkyl group, halogen atoms and oxo group as a substituent on the indoline ring), for example, an indolinin-1 -ila group, indolinin-2- group ila, indolinin-3-ila group, indolinin-4-ila group, indolinin-5-ila group, indolinin-6-ila group, indolinin-7-ila group, 3methyl-indolin-1-ila group, group 3.8 -dibromoindolin-1-yl, group 2-oxoindolin-1-yl (other name: ooxyindol-1-yl group), 3-methyl-2-oxoindolin-1-yl group, 3,3-dimethyl-2oxoindolin-1 group -ila, 3-ethyl-2-oxoindolin-1-yl group, 3-n-propyl-2-oxoindolin-1-yl group, 3-n-butyl-2-oxoindolin-1-yl group, 3-n group -pentyl-2-oxoindolin-1-yl, group 3-fluoro2-oxoindolin-1-yl, group 3,3-difluoro-2-oxoindolin- 1-yl, 3-chloro-2-oxoindolin-1yl group, 3,3-dichloro-2-oxoindolin-1-yl group or the like.

[0375] An example of a 2,3-dihydrobenzisothiazolyl group (which may have at least one oxo group as a substituent on the 2,3-dihydrobenzisothiazole ring) includes a 3-benzisothiazolidinon-1,1-dioxide-2-yl group or similar.

[0376] Examples of a 1 H-2,4-benzoxazinyl group (which may have at least one oxo group as a substituent on the 1 H-2,4-benzoxazine ring) include a 1 H-2,4-benzoxazin group 3 (4H) -on-4-yl, group 1 H-2,4-benzoxazin-1,3 (4H) -dion-4-yl or the like.

[0377] A C1-6 alkyl phenoxy group that can have a halogen atom as a substituent on the phenyl ring includes a C1-6 alkyl phenoxy group that can have 1 to 5 halogen atoms, for example, a phenoxymethyl group, group 2-fluorophenoxymethyl, group 3-fluorophenoxymethyl, group 3,4-difluorophenoxymethyl, group

3,5-difluorophenoxymethyl, group 2,3,4,5,6-pentafluorophenoxymethyl, group 2

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285/854 chlorophenoxymethyl, group 3-chlorophenoxymethyl, group 4-chlorophenoxymethyl, group 3,4dichlorophenoxymethyl, group 3,5-dichlorophenoxymethyl, group 2-phenoxyethyl [la], group 1-phenoxyethyl [la], group 3-phenoxypropyl, group 4-phenoxypropyl , group 5-phenoxypentyl, group 6-phenoxy, group 2- (2,4,6-chlorophenoxy) ethyl, group 3- (4-iodophenoxy) propyl, group 4- (4bronophenoxy) butyl, group 5- (4-chlorophenoxy ) pentyl, group 6- (4-chlorophenoxy) hexyl or the like.

[0378] A C2-6 phenyl alkenyl group that can have a halogen atom as a substituent on the phenyl ring includes a C2-6 phenyl alkenyl group that has 1 to 2 double bonds and can have 1 to 5 halogen atoms as a substituent on the phenyl ring, for example, a 3-phenyl-2-propenyl group (common name: cinamyl group), 4-phenyl-2-butenyl group, 4-phenyl-3-butenyl group, 4-phenyl-1, 3butadienyl, 5-phenyl-1,3,5-hexathrienyl group, 3- (2-fluorophenyl) -2-propenyl group, group

3- (3-fluorophenyl) -2-propenyl, group 3- (4-fluorophenyl) -2-propenyl, group 3- (2,3difluorophenyl) -2-propenyl, group 3- (2,3,4,5, 6-pentafluorophenyl) -2-propenyl, group 3 (3,4-difluorophenyl) -2-propenyl, group 3- (3,5-difluorophenyl) -2-propenyl, group 3- (2,4,6trichlorophenyl) -2 -propenyl, group 3- (3-chlorophenyl) -2-propenyl, group 3- (4-chlorophenyl) -2propenyl, group 3- (2,3-dichlorophenyl) -2-propenyl, group 3- (2,4- dichlorophenyl) -2-propenyl, group 3- (3,4-dichlorophenyl) -2-propenyl, group 3- (3,5-dichlorophenyl) -2-propenyl, group 3 (2-bromophenyl) -2-propenyl, group 3- (3-bromophenyl) -2-propenyl, group 3- (4bromophenyl) -2-propenyl, group 4- (4-chlorophenyl) -2-butenyl, group 4- (4-chlorophenyl) -3butenyl, group 5- (4-chlorophenyl) -2-pentenyl, group 5- (4-chlorophenyl) -4-pentenyl, group 5 (4-chlorophenyl) -3-pentenyl, group 6- (4-chlorophenyl) -5-hexenyl, group 6 - (4-chlorophenyl) -4hexenyl, group 6- (4-chlorophenyl) -3-hexenyl, group 6- (4-chlorophenyl) -3-hexenyl or the like.

[0379] A phenyl group that can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group, unsubstituted C1-6 alkoxy group or substituted by halogen and phenyl group as a substituent includes a phenyl group which can be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1 alkyl group

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286/854 unsubstituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen and phenyl group as a substituent, for example, a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3bromophenyl group, 4-bromophenyl group, 2-iodophenyl group, 3-iodophenyl group, 4iodophenyl group, 2,3-difluorophenyl group, 3,4 group -difluorophenyl, 3,5-difluorophenyl group, 2,4-difluorophenyl group, 2,6-difluorophenyl group, 2,3-dichlorophenyl group, 3,4dichlorophenyl group, 3,5-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4,5-trifluorophenyl group, 3,4,5-trichlorophenyl group, 2,4,6-trifluorophenyl group, group

2,4,6-trichlorophenyl, 2-fluoro-4-bromophenyl group, 4-chloro-3-fluorophenyl group, 2,3,4-trichlorophenyl group, 3,4,5-trifluorophenyl group, 2,4,6- triburomophenyl, 4-n-butylphenyl group, 2,4-dimethylphenyl group, 2,3-dimethylphenyl group, 2,6-dimethylphenyl group, 3,5-dimethylphenyl group, 2,5-dimethylphenyl group, 2,4,6-trimethylphenyl group , 3,5ditrifluoromethylphenyl group, 4-n-butoxyphenyl group, 2,4-dimethoxyphenyl group, 2,3-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2,5dimethoxyphenyl group, group 2,4,6 -trimethoxyphenyl, 3,5-ditrifluoromethoxyphenyl group, 3-chloro-4-methoxyphenyl group, 2-chloro-4-trifluoromethoxyphenyl group, 3-methyl-4-fluorophenyl group, 4-bromo-3-trifluoromethylphenyl group, 2-methylphenyl group, group 3-methylphenyl, 4methylphenyl group, 2-methyl-3-chlorophenyl group, 3-methyl-4-chlorophenyl group, 2-chloro-4methylphenyl group, 2-methyl-3-fluorophenyl group, 2-trifluoromethylphenyl group, 3trifluoromethylphenyl group, group 4-trifluoromethylphenyl, group 2-pen tafluoroethylphenyl, 3pentafluoroethylphenyl group, 4-pentafluoroethylphenyl group, 2-isopropylphenyl group, 3isopropylphenyl group, 4-isopropylphenyl group, 2-ter-butylphenyl group, 3-ter-butylphenyl group, 4-ter-butyl group, 2-ter-butyl group , 3-sec-butylphenyl group, 4-secbutylphenyl group, 2-n-heptafluoropropylphenyl group, 3-n-heptafluoropropylphenyl group, group

4-n-heptafluoropropylphenyl, group 4-pentylphenyl, group 4-hexylphenyl, group 2-methoxyphenyl, group 3-methoxyphenyl, group 4-methoxyphenyl, group 3-chloro-2-methoxyphenyl, group 2-fluoro-3-methoxyphenyl, group 2- fluoro-4-methoxyphenyl, group 2,6-dimethoxyphenyl, group 2,3,4-trifluorophenyl, group 2,3,4,5,6-pentafluorophenyl, group 2trifluoromethoxyphenyl, group 3-trifluoromethoxyphenyl, group 4-trifluoromethoxyphenyl, group

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287/854

3-fluoro-2-trifluoromethoxyphenyl, 2-fluoro-3-trifluoromethoxyphenyl group, 3-fluoro-4trifluoromethoxyphenyl group, 3-chloro-2-tnfluoromethoxyphenyl group, 2-chloro-3trifluoromethoxyphenyl group, 3-chloro-methoxyphenyl group 2pentafluoroethoxyphenyl, 3-pentafluoroethoxyphenyl group, 4-pentafluoroethoxyphenyl group, 3-chloro-2-pentafluoroethoxyphenyl group, 2-chloro-3-pentafluoroethoxyphenyl group, 3chloro-4-pentafluoroethoxyphenyl group, 2-isopropoxy group, 4-isopropoxy group isopropoxyphenyl, group 2-ter-butoxyphenyl, group 3-ter-butoxyphenyl, group 4-terbutoxyphenyl, group 2-sec-butoxyphenyl, group 3-sec-butoxyphenyl, group 4-secbutoxyphenyl, group 2-n-heptafluoropropoxyphenyl, group 3- n-heptafluoropropoxyphenyl, group 4-n-heptafluoropropoxyphenyl, group 4-n-pentoxiphenyl, group 4-n-hexyloxyphenyl,

4- biphenylyl, group 3-biphenylyl, group 2-biphenylyl or similar.

[0380] A 1,3-thiazolidinyl group (which can be substituted on the 1,3-thiazolidine ring by at least one group selected from a group consisting of an oxo group and phenyl C1-6 alkylidene group which may have an alkyl group C1-6 unsubstituted or substituted by halogen in the phenyl group as a substituent) includes a group

1.3- thiazolidinyl (which can be substituted on the 1,3-thiazolidine ring by 1 to 3 groups selected from a group consisting of an oxo group and phenyl C 1 -6 alkylidene group which can [be] 1 to 3 C 1-6 alkyl groups unsubstituted or substituted by halogen as a substituent on the phenyl group), for example, a 1,3-thiazolidine-2-yl group, 1,3-thiazolidine-3-yl group, 1,3-thiazolidine-4-yl group, group 1,3thiazolidino-5-yl, 1,3-thiazolidino-2,4-dion-3-yl group, 5-benzylidene-1,3thiazolidine-3-yl group, 5-benzylidene-1,3-thiazolidine-2 group -on-3-yl, 5-benzylidene- group

1.3- thiazolidine-4-on-3-yl, group 5- (2-methylbenzylidene) -1,3-thiazolidine-3-yl, group 5 (2,4-dimethylbenzylidene) -1,3-thiazolidine-3-yl , group 5- (2,4,6-trimethylbenzylidene) -1,3thiazolidine-3-yl, group 5-benzylidene-1,3-thiazolidine-2,4-dion-3-yl, group 5- (2-trifluoromethylbenzylidene ) -1,3-thiazolidine-2,4-dion-3-yl, group 5- (3,5ditrifluoromethylbenzylidene) -1,3-thiazolidine-2,4-dion-3-yl, group 5- (4tritnfluoromethylbenzylidene) - 1,3-thiazolidine-2,4-dion-3-yl, group 5- [2- (4tritrifluoromethylphenyl) ethylidene] -1,3-thiazolidine-2,4-dion-3-yl, group 5- [3- (4tritrifluoromethylphenyl) propylidene] -1,3-thiazolidine-2,4-dion-3-yl, group 5- [4- (4Petition 870190039560, from 26/04/2019, page 296/876

288/854 tritrifluoromethylphenyl) butylidene] -1,3-thiazolidine-2,4-dion-3-yl, group 5- [5- (4tritrifluoromethylphenyl) pentylidene] -1,3-thiazolidine-2,4-dion-3- ila, group 5- [6- (4trifluoromethylphenyl) hexylidene] -1,3-thiazolidine-2,4-dion-3-yl or the like.

[0381] A phenyl group unsubstituted or substituted by halogen includes a phenyl group that can be substituted by 1 to 5 halogen atoms, for example, a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group , group 2-chlorophenyl, group 3-chlorophenyl, group 4-chlorophenyl, group 2-bromophenyl, group 3bromophenyl, group 4-bromophenyl, group 2-iodophenyl, group 3-iodophenyl, group 4iodophenyl, group 2,3-difluorophenyl, group 3,4-difluorophenyl, 3,5-difluorophenyl group, 2,4-difluorophenyl group, 2,6-difluorophenyl group, 2,3-dichlorophenyl group, 3,4dichlorophenyl group, 3,5-dichlorophenyl group, 2,4 group -dichlorophenyl, 2,6-dichlorophenyl group, 3,4,5-trifluorophenyl group, 3,4,5-trichlorophenyl group, 2,4,6-trifluorophenyl group, group

2.4.6- trichlorophenyl, group 2-fluoro-4-bromophenyl, group 4-chloro-3-fluorophenyl, group 2,3,4-trichlorophenyl, group 3,4,5-trifluorophenyl, group 2,4,6-trifluorophenyl group

2.3.4.5.6- pentafluorophenyl or similar.

[0382] A phenyl C1-6 alkyl group that may have a phenyl group as a substituent on the phenyl ring includes a phenyl C1-6 alkyl group that may have 1 to 3 phenyl groups as a substituent on the phenyl ring, for example, a benzyl group, 2-phenylethyl, group 1-phenylethyl, group 3-phenylpropyl, group 4-phenylbutyl, group 5-phenylpentyl, group 6-phenylexyl, 2-methyl-3-phenylpropyl, group 1,1-dimethyl 2-phenylethyl, group 3 -phenylbenzyl, group 2-phenylbenzyl, group 4-phenylbenzyl, group 2,4diphenylbenzyl, group 2,4,6-triphenylbenzyl or the like.

[0383] A phenyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group and unsubstituted C1-6 alkoxy group or substituted by halogen, amino group (which can be substituted in the amino group by at least one group selected from a group consisting of a C1-6 alkyl group and phenyl group (which can be substituted in the phenyl ring by at least one selected group) of a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group not

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289/854 substituted or substituted by halogen), phenoxy group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and group C1-6 alkoxy unsubstituted or substituted by halogen) and piperidyl group (which can be substituted on the piperidine ring by at least one phenoxy group as a substituent (which can be substituted by at least one group selected from a group consisting of an atom halogen, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen))) includes a phenyl group (which can be substituted on the phenyl ring by 1 to 5, preferably from 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and unsubstituted C1-6 alkoxy group or substituted by halogen, amino group (which can be substituted in the amino group by 1 to 2 groups selected from a group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted in the phenyl ring by 1 to 5 , preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen), phenoxy group (which may be substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group or halogen and unsubstituted C1-6 alkoxy group or substituted by halogen) and piperidyl group (which can be substituted on the piperidine ring by 1 to 3 phenoxy groups, as a substituent, (which can be substituted by 1 to 5, preferably 1 to 3 groups selected from a group q ue consists of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen))), for example, a phenyl group, 2-fluorophenyl group, group 3- fluorophenyl, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-iodophenyl group, 3iodophenyl group, 4-iodophenyl group, 2,3-difluorophenyl group, 2,3,4,5,6pentafluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, group 2,4

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290/854 difluorophenyl, group 2,6-difluorophenyl, group 2,3-dichlorophenyl, group 3,4-dichlorophenyl, group 3,5-dichlorophenyl, group 2,4-dichlorophenyl, group 2,6-dichlorophenyl, group 3, 4,5trifluorophenyl, 3,4,5-trichlorophenyl group, 2,4,6-trifluorophenyl group, 2,4,6trichlorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4dimethylphenyl group, group 2,4,6-trimethylphenyl, 2-methyl-3-chlorophenyl group, 3-methyl-4-chlorophenyl group, 2-chloro-4-methylphenyl group, 2-methyl-3-fluorophenyl group, 2trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 3,5-di (trifluoromethyl) phenyl, 4trifluoromethylphenyl group, 2-pentafluoroethylphenyl group, 3-pentafluoroethylphenyl group, 4pentafluoroethylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 4isopropylphenyl group, 3-ispropylphenyl group -butylphenyl, group 4-ter-butylphenyl, group 2-sec-butylphenyl, group 3-sec-butylphenyl, group 4-sec-butylphenyl, group 2-nheptafluoropropylphenyl, group 3-n-hept afluoropropylphenyl, group 4-nheptafluoropropylphenyl, group 4-pentylphenyl, group 4-hexylphenyl, group 2-methoxyphenyl, group 3-methoxyphenyl, group 4-methoxyphenyl, 2-methoxy-3-chlorophenyl, group 2-fluoro-3-methoxyphenyl fluoro-4-methoxyphenyl, 2,6-dimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, 2-trifluoromethoxyphenyl group, 3-trifluoromethoxyphenyl group, 4trifluoromethoxyphenyl group, 3,5-ditrifluoromethoxyphenyl group, 2-trifluoromethoxyphenyl group, 2-trifluoromethoxyphenyl group, 2-group 3-pentafluoroethoxyphenyl group, 4pentafluoroethoxyphenyl group, 2-isopropoxyphenyl group, 3-isopropoxyphenyl group, 4isopropoxyphenyl group, 2-ter-butoxyphenyl group, 3-ter-butoxyphenyl group, 3-terbutoxyphenyl group, 2-sec-butox group, 3-sec-butox group sec-butoxyphenyl, 4-secbutoxyphenyl group, 2-n-heptafluoropropoxyphenyl group, 3-n-heptafluoropropoxyphenyl group, 4-n-heptafluoropropoxyphenyl group, 4-pentyloxyphenyl, 4-hexyloxyphenyl group, 2aminophenyl-aminophenyl, group 3-aminophenyl, group 3 group 3-methylaminophenyl, 3-dimethylaminophenyl group, 4-methylaminophenyl group, 4-dimethylaminophenyl group, 4-ethylaminophenyl group, 4-diethylaminophenyl group, 4-di-n-propylaminophenyl group, 4-n-propylaminophenyl group, 4-n-n-group butylaminophenyl, 4-di-n-butylaminophenyl group, 4-n-pentylaminophenyl group, 4-di-n-pentylaminophenyl group, 4-nhexylaminophenyl group, 4-di-n-hexylaminophenyl group, 4-phenylaminophenyl group, group 4- ( 2fluorophenylamino) phenyl, group 4- (3-fluorophenylamino) phenyl, group 4- (4Petition 870190039560, from 26/04/2019, p. 299/876

291/854 fluorophenylamino) phenyl, group 4- (2,3,4,5,6-pentafluorophenylamino) phenyl, group 4- (2,4-

difluorophenylamino) phenyl, group 4- (3,4-difluorophenylamino) phenyl, group 4- (3.5- difluorophenylamino) phenyl, group 4- (2-chlorophenylamino) phenyl, group 4- (3- chlorophenylamino) phenyl, group 4- (4-chlorophenylamino) phenyl, group 4- (2- bromophenylamino) phenyl, group 4- (3-bromophenylamino) phenyl, group 4- (4- bromophenylamino) phenyl, group 4- (2,3-dichlorophenylamino) phenyl, group 4- (2,4- dichlorophenylamino) phenyl, group 4- (2,4,6-trichlorophenylamino) phenyl, group 4- (3.5- dichlorophenylamino) phenyl, group 4- (2-methylphenylamino) phenyl, group 4- (3- methylphenylamino) phenyl, group 4- (4-methylphenylamino) phenyl, group 4- (2-

ethylphenylamino) phenyl, group 4- (3-ethylphenylamino) phenyl, group 4- (4-ethyl-phenylamino) phenyl, group 4- (4-n-propylphenylamino) phenyl, group 4- (4-ter-butylphenylamino) phenyl, group 4 - (4-nbutylphenylamino) phenyl, group 4- (2-trifluoromethylphenylamino) phenyl, group 4- (3-trifluoromethylphenylamino) phenyl, group 4- (4-trifluoromethylphenylamino) phenyl, group 4- (2pentafluoroethylphenylamino) 3- group, 4- pentafluoroethylphenylamino) phenyl, group 4 (2,3-dimethylphenylamino) phenyl, group 4- (3,4,5-trimethylphenylamino) phenyl, group 4- (4pentylphenylamino) phenyl, group 4- (4-hexylphenylamino) phenyl, group 4- (2trifluoromethoxyphenylamino) phenyl, group 4- (3-trifluoromethoxyphenylamino) phenyl, group 4 (3-methoxyphenylamino) phenyl, group 4- (2,4-dimethoxyphenylamino) phenyl, group 4- (2,4,6trimethoxyphenylamino) phenyl, group 4 - (4-trifluoromethoxyphenylamino) phenyl, group 4- (2pentafluoroethoxyphenylamino) phenyl, group 4- (3-pentafluoroethoxyphenylamino) phenyl, group

4- (4-pentafluoroethoxyphenylamino) phenyl, group 3- (N-methyl-N-phenylamino) phenyl, group 2-phenoxyphenyl, group 3-phenoxyphenyl, group 4-phenoxyphenyl, group 2- (2-chlorophenoxy) phenyl, group 2.4 -diphenoxyphenyl, group 2- (3-chlorophenoxy) phenyl, group 2- (4-chlorophenoxy) phenyl, group 3- (2-chlorophenoxy) phenyl, group 3- (3-chlorophenoxy) phenyl, group 3- (4 chlorophenoxy) phenyl , group 4- (2-chlorophenoxy) phenyl, group 4- (2,3-dichlorophenoxy) phenyl, group 4- (2,4,6-trichlorophenoxy) phenyl, group 2- (2-trifluoromethylphenoxy) phenyl, group 2- (3trifluoromethylphenoxy) phenyl, group 2- (4-trifluoromethylphenoxy) phenyl, group 3- (2trifluoromethylphenoxy) phenyl, group 3- (3-trifluoromethylphenoxy) phenyl, group 3- (2,3,4,5,6pentafluoromethylphenoxy) phenyl, group 4- (2-trifluoromethylphenoxy) phenyl, group 4- (3-trifluoromethylphenoxy) phenyl, group 4- (2,4-dimethylphenoxy) phenyl, group 4- (2,4,6

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292/854 trimethylphenoxy) phenyl, group 4- (3-trifluoromethylphenoxy) phenyl, group 4- (4-trifluoromethylphenoxy) phenyl, group 2- (2-trifluoromethoxyphenoxy) phenyl, group 2- (3-trifluoromethoxyphenoxy) phenyl, group 2- (4-trifluomethylphenoxy) ) phenyl, group 2- (4methoxyphenoxy) phenyl, group 2- (2,4-dimethoxyphenoxy) phenyl, group 2- (2,4,6trimethoxyphenoxy) phenyl, group 3- (2-trifluoromethoxyphenoxy) phenyl, group 3- (3trifluoromethoxyphenoxy ) phenyl, group 3- (4-trifluoromethoxyphenoxy) phenyl, group 4- (2-trifluoromethoxyphenoxy) phenyl, group 4- (3-trifluoromethoxyphenoxy) phenyl, group 4- (4trifluoromethoxyphenoxy) phenyl, phenoxypiperidin-1-yl) phen ia, group 2- (4-phenoxypiperidin-1-yl) phenyl, group 3- (4 group 4- (4-phenoxypiperidin-1-yl) phenyl, group 2- [4- (4 chlorophenoxy) piperidin-1-yl] phenyl, group 4- [4- (4-chlorophenoxy) piperidin-1-yl] phenyl, group 3 [4- (2,4,6-trichlorophenoxy) pipendin-1-yl] phenyl, group 4- [4- (3, 4-dichlorophenoxy) piperidin-1 yl] phenyl, group 4- [4- (2,3,4,5,6-pentafluorophenoxy) piperidin-1-yl] phenyl, group o 4- [4- (4bromophenoxy) piperidin-1-yl] phenyl, group 3- [4- (4-chlorophenoxy) piperidin-1-yl] phenyl, group 2- [4- (4-methylphenoxy) piperidin-1 -yl] phenyl, group 2- [4- (3,4-dimethylphenoxy) piperidin-1 yl] phenyl, group 2- [4- (3,4,5-trimethylphenoxy) piperidin-1-yl] phenyl, group 3- [4- (4trifluoromethylphenoxy) piperid in-1 -yl] phenyl, group 4- [4- (4-trifluoromethylphenoxy) pipendin-1 yl] phenyl, group 3- [4- (4-pentafluoroethylphenoxy) piperidin -1-yl] phenyl, group 4- [4- (4pentafluoroethylphenoxy) piperidin-1-yl] phenyl, group 2- [4- (4-trifluoromethoxyphenoxy) pipendin1-yl] phenyl, group 3- [4- (4- trifluoromethoxyphenoxy) pipendin-1-yl] phenyl, group 4- [4- (4methoxyphenoxy) piperidin-1 -yl] phenyl, group 4- [4- (2,4-dimethoxyphenoxy) piperidin-1-yl] phenyl, group 4 - [4- (2,4,6-trimethoxyphenoxy) pipendin-1-yl] phenyl, group 4- [4- (4trifluoromethoxyphenoxy) pipendin-1-yl] phenyl, group 2- [4- (4pentafluoroethoxyphenoxy) piperidin-1 -il] phenyl, group

4- [4- (4pentafluoroethoxyphenoxy) piperidin-1-yl] phenyl, group (3,4-diphenoxypiperidin-1-yl) phenyl, group piperidin-1-ylphenyl, group (3,4,5-triphenoxypiperidin -1 -yl) phenyl, piperidin-4-ylphenyl group or the like.

[0384] A C1-6 alkyl piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from a group consisting of a C1-6 alkoxycarbonyl group and a C1-6 phenyl alkoxycarbonyl group that can be substituted on the ring phenyl by 1 to 3 groups selected from a group consisting of

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293/854 of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen or C1-6 alkoxy group unsubstituted or substituted by halogen and phenyl group) includes a piperazinyl C1-6 alkyl group (which can be substituted in piperazine ring by 1 to 3 groups selected from a group consisting of a C1-6 alkoxycarbonyl group and a C1-6 phenyl alkoxycarbonyl group that can be replaced on the phenyl ring by 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen or C1-6 alkoxy group unsubstituted or substituted by halogen and phenyl group), for example, a 1-piperazinylmethyl group, 2- (2-piperazinyl) ethyl group , group 1- (3-piperazinyl) ethyl, group 3- (4-piperazinyl) propyl, group 4- (1-piperazinyl) butyl, group 5- (2piperazinyl) pentyl, group 6- (3-piperazinyl) hexyl, group 4-methoxycarbonyl-1piperazinylmethyl, group 2- (4-methoxycarbonyl-1-piperazin yl) ethyl, group 3- (4-methoxycarbonyl-1-piperazinyl) propyl, group 4- (4-methoxycarbonyl-1-piperazinyl) butyl, group 5- (4-methoxycarbonyl-1-piperazinyl) pentyl, group 6 - (4-methoxycarbonyl-1piperazinyl) hexyl, group 4-ethoxycarbonyl-1-piperazinylmethyl, group 2- (4-ethoxycarbonyl1-piperazinyl) ethyl, group 3- (4-ethoxycarbonyl-1-piperazinyl) propyl, group 4- (4ethoxycarbonylyl) -1-piperazinyl) butyl, group 5- (4-ethoxycarbonyl-1-piperazinyl) pentyl, group

6- (4-ethoxycarbonyl-1-piperazinyl) hexiIa, group 4-ter-butoxycarbonyl-1-piperazinylmethyl, group 2- (4-ter-butoxycarbonyl-1-piperazinyl) ethyl, group 3- (4-ter-butoxycarbonyl- 1piperazinyl) propyl, group 4- (4-ter-butoxycarbonyl-1-piperazinyl) butyl, group 5- (4-terbutoxycarbonyl-1-piperazinyl) pentyl, group 6- (4-ter-butoxycarbonyl-1-piperazinyl) hexiIa, group 2- (4-biphenylylmethoxycarbonyl-1-piperazinyl) ethyl, group 3- (4-biphenylylmethoxycarbonyl1-piperazinyl) propyl, group 4- (4-biphenylylmethoxycarbonyl-1-piperazinyl) butyl, group 5- (4biphenylylmethoxycarbonyl-1 ) pentyl, group 6- (4-biphenylylmethoxycarbonyl-1 piperazinyl) hexyl, group 2- (4-benzyloxycarbonyl-1-piperazinyl) ethyl, group 3- (4benzyloxycarbonyl-1-piperazinyl) propyl, group 4- (4 -benzyloxycarbonyl-1 - piperazinyl) butyl, group 5- (4-benzyloxycarbonyl-1-piperazinyl) pentyl, group 6-4- (4benzyloxycarbonyl) -1 -piperazinyl) hexi la, group 2- (4- (2-fluorobenzyloxycarbonyl) ) -1 piperazinyl) ethyl, group 3- (4- (2-fluorobenzyloxic arbonyl) -1-piperazinyl) propyl, group 4 (4- (2,3-difluorobenzyloxycarbonyl) -1-piperazinyl) butyl, group 5- (4- (2Petition 870190039560, from 26/04/2019, p. 302/876

294/854 fluorobenzyloxycarboni 1) -1-piperazinyl) pentyl, group 6- (4- (4-fluorobenzyloxycarbonyl) -1 piperazinyl) hexyl, group 3- (4- (3-fluorobenzyloxycarbonyl) -1-piperazinyl) propyl, group 4 (4- (3-fluorobenzyloxycarbonyl) -1-piperazinyl) butyl, group 5- (4- (3-fluorobenzyloxycarbonyl) -1 -piperazinyl) pentyl, group 3- (4- (4-fluorobenzyloxycarbonyl) -1 piperazinyl) propyl, group 4- (4- (4-fluorobenzyloxycarbonyl) -1-piperazinyl) butyl, group 5 (4- (4-fluorobenzyloxycarbonyl) -1 -piperazin) pentyl, group 6- (4- (4fluorobenzyloxycarbonyl) -1 -piperazinyl ) hexyl, group 2- (4- (2,3-dichlorobenzyloxycarbonyl) 1-piperazinyl) ethyl, group 3- (4- (2-chlorobenzyloxycarbonyl) -1-piperazinyl) propyl, group 4 (4- (2-chlorobenzyloxycarbonyl) -1-piperazinyl) butyl, group 5- (4- (2,4,6trichlorobenzyloxycarbonyl) -1 -piperazinyl) pentyl, group 6- (4- (2-chlorobenzyloxycarbonyl) -1 piperazinyl) hexyl, group 2- ( 4- (3-chlorobenzyloxycarbonyl) -1-piperazinyl) ethyl, group 3- (4 (3-chlorobenzyloxycarbonyl) -1-piperazinyl) propyl, group 4- (4- (3 (trichlorobenzyloxycarbonyl) -1-piperazinyl) butyl, group 5- (4- (3-chlorobenzyloxycarbonyl) -1 piperazinyl) pentyl, group 6- (3-chloro-4-methylbenzyloxycarbonyl-1-piperazinyl) hexyl, group 2- (4- (4-chlorobenzyloxycarbonyl) -1-piperazinyl) ethyl, group 3- (4- (4-chlorobenzyloxycarbonyl) -1 -piperazinyl) propyl, group 4- (4- (4-chloro-3methoxybenzyloxycarbonyl) ) -1-piperazinyl) butyl, group 5- (4- (4-chlorobenzyloxycarbonyl) -1 piperazinyl) pentyl, group 6- (4-chlorobenzyloxycarbonyl-1-piperazinyl) hexyl, group 2- (4-

(2-methylbenzyloxycarbonyl) -1-piperazinyl) methyl, group 2- (4- (2,4- dimethylbenzyloxycarbonyl) -1-piperazinyl) methyl, group 2- (4- (2,4,6- trimethylbenzyloxycarbonyl) -1-piperazinyl) methyl, group 2- (4- (2- trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) ethyl, group 3- (4- (3,5- ditrifluoromethylbenzyloxycarbonyl) -1-piperazinyl) propyl, group 4- (4- (2- trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) butyl, group 5- (4- (2- trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) pentyl, group 6- (4- (2- trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) hexyl, group 3- (4- (3- trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) propyl, group 4- (4- (3- trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) butyl, group 5- (4- (3- trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) pentyl, group 3- (4- (4- trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) propyl, group 4- (4- (4-

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295/854 trifluoromethyl Ibenzi loxycarbon i 1) -1-piperazinyl) butyl, trifluoromethylbenzyloxycarbonyl) -1 -piperazinyl) pentyl, trifluoromethylbenzyloxycarbonyl) -1 -piperazinyl) hexi la, ditrifluoxycarbonyl group il) ethyl, methoxybenzyloxycarbonyl) -1-piperazinyl) methyl group, dimethoxybenzyloxycarbonyl) -1-piperazinyl) methyl group, trimethoxybenzyloxycarbonyl) -1-piperazinyl) methyl, trifluoromethoxybenzyloxycarbonyl) -1-piperazinyl group) -tripluoromethanyl) propyl -1-piperazinyl) butyl, trifluoromethoxybenzyloxycarbonyl) -1 -piperazinyl) pentyl, trifluoromethoxybenzyloxycarbonyl) -1 -piperazinyl) -1 -piperazinyl) trifluoromethoxybenzyloxycarbonyl) -1 -piperazinyl) -1-piperazinyl) trifluoxycarbonyl group -piperazinyl) butyl, trifluoromethoxybenzyloxycarbonyl) -1 -piperazinyl) pentyl, trifluoromethoxybenzyloxycarbonyl) -1 -piperazinyl) propyl, trifluoromethoxybenzyloxic group arbonyl) -1-piperazin i l) butyl, trifluoromethoxybenzyloxycarbonyl) -1-piperazin i l) pentyl group

5- (4- (4-

6- (4- (4-

2- (4- (3,5-

2- (4- (2-

2- (4- (2,42- (4- (2,4,6-

3- (4- (2-

4- (4- (2-

5- (4- (2-

6- (4- (2-

3- (4- (3-

4- (4- (3-

5- (4- (3-

3- (4- (4-

4- (4- (4-

5- (4- (4-

6- (4- (4- trifluoromethoxybenzyloxycarbonyl) -1-piperazinyl) hexyl, group (3,4-diethoxycarbonyl-1piperazinyl) methyl, group 4-phenylmethoxycarbonyl-2,5-dimethoxycarbonyl-1-piperazini I) methyl or the like.

[0385] A C1-6 alkyl piperazinylcarbonyl group (which can be substituted on the piperazine ring by at least one group selected from a group consisting of a C1-6 alkoxycarbonyl group, a C1-6 alkoxycarbonyl phenyl group that may have an alkyl group C1-6 unsubstituted or substituted by halogen as a substituent on the phenyl ring and phenyl C1-6 alkyl group which may have at least one group selected from a group consisting of an unsubstituted or substituted C1-6 alkyl group and halogen and group phenyl as a substituent on the phenyl ring) includes a C1-6 alkyl piperazinylcarbonyl group (which can be substituted on the piperazine ring by 1 to 3 groups selected from a group consisting of a C1-6 alkoxycarbonyl group, a C1- phenyl alkoxycarbonyl group 6 that can have 1 to 3 alkyl groups

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296/854

C1-6 unsubstituted or substituted by halogen as a substituent on the phenyl ring and phenyl C1-6 alkyl group which may have 1 to 3 groups selected from a group consisting of an unsubstituted or substituted C1-6 alkyl group and halogen and phenyl group as a substituent on the phenyl ring), for example, a group

1 -piperazinylcarbonylmethyl, group 2- (2-piperazinylcarbonyl) ethyl, group 1- (3- piperazinylcarbonyl) ethyl, group 3- (4-piperazinylcarbonyl) propyl, group 4- (1- piperazinylcarbonyl) butyl, group 5- (2-piperazinylcarbonyl) pentyl, group 6- (3-

piperazinylcarbonyl) hexyl, 4-ter-butoxycarbonyl-1-piperazinylcarbonylmethyl group, group

2- (4-ter-butoxycarbonyl-1-piperazinylcarbonyl) ethyl, group 3- (4-ter-butoxycarbonyl-1 piperazinylcarbonyl) propyl, group 4- (4-ter-butoxycarbonyl-1-piperazinylcarbonyl) butyl, group 5- (4-ter-butoxycarbonyl-1-piperazinylcarbonyl) pentyl, group 6- (4-terbutoxycarbonyl-1-piperazinylcarbonyl) hexyl, group 4-ethoxycarbonyl-1 - piperazinylcarbonylmethyl, group 2- (4-ethoxycarbonyl-1-piperazinylcarbonyl ) ethyl, group 3 (4-n-propoxycarbonyl-1-piperazinylcarbonyl) propyl, group 4- (4-ethoxycarbonyl-1 piperazinylcarbonyl) buty, group 5- (4-n-pentyloxycarbonyl-1-piperazinylcarbonyl) pentyl, group 6- (4-n-hexyloxycarbonyl-1-piperazinylcarbonyl) hexyl, group 4- (benzyloxycarbonyl) 1-piperazinylcarbonylmethyl, group 2- (4-benzyloxycarbonyl) -1-piperaziniIcarbonyl) ethyl, group 3- (4- (benzyloxycarbonyl) -1- piperazinylcarbonyl) propyl, group 4- (4 (benzyloxycarbonyl) -l -pi perazinylcarbonyl) butyl, group 5- (4-benzyloxycarbonyl) -1 piperazinylcarbonyl) pentyl, group 6- (4- (benzyloxycarbonyl) -1 - piperazinylc arbonyl) hexyl, group 4- (4-methylbenzyloxycarbonyl) -1-piperazinylcarbonylmethyl, group 4- (2,4dimethylbenzyloxycarbonyl) -1 -piperazinylcarbonylmethyl, group 4- (2,4,6trimethylbenzyloxycarbonyl) -1 -piperazinylcarbonylmethylcarbonylmethyl, 4-group ) -1-piperazinylcarbonylmethyl, group 2- (4- (3,5ditrifluoromethylbenzyloxycarbonyl) -1 -piperazinylcarbonyl) ethyl, group 3- (4- (4trifluoromethylbenzyloxycarbonyl) -1 -piperazinylcarbonyl) propyl, group 4- (4- (4trifluoromethylbenzyloxycarbonyl) -1-piperazinylcarbonyl) butyl, group 5- (4- (4trifluoromethylbenzyloxycarbonyl) -1 -piperazinylcarbonyl) pentyl, group 6- (4- (4trifluoromethylbenzyloxycarbonyl) -1 -piperazinylcarbonyl 2phenylethoxycarbonyl) -1-piperazinylcarbonylmethyl, group 2- {4- [2- (4Petition 870190039560, from 26/04/2019, p. 305/876

297/854 trifluoromethyl Ifenyl) ethoxycarbonyl] -1-piperazinyl Icarbonyl} ethyl, group 3- {4- [2- (4trifluoromethylphenyl) ethoxycarbonyl] -1 -piperazin i Icarbon i IJpropylene, group 4- { 4- [2- (4methylphenyl) ethoxycarbonyl] -1 -piperazinylcarbonyl, group 5- {4- [2- (2,4,6trimethyl) ethoxycarbonyl] -1 -piperazinyl Icarbonyl , group 6- {4- [2- (4trifluoromethylphenyl) ethoxycarbonyl] -1-piperazinylcarbonyljhexyl, group 4-benzyl-1 piperazinylcarbonylmethyl, group 4- (4-trifluoromethylbenzyl) -1 -piperazinylcarbonylmethyl, group 2- (4- (4- (4- trifluoromethylbenzyl) -1-piperazinylcarbonyl) ethyl, group 3- (4- (4trifluoromethyl Ibenzi 1) -1 -piperazinylcarbonyl) propyl, group 4- (4-methylbenzyl) -1 piperazinylcarbonylmethyl, group 4- (2,4-dimethylbenzyl) -1-piperazinylcarbonylmethyl, group 4- (2,4,6-trimethylbenzyl 1) -1 -piperazinylcarbonylmethyl, group 4- (4- (4-trifluoromethylbenzyl) -1 piperazinylcarbonyl) butyl, group 5- (4- ( 3,5-ditrifluoromethylbenzi 1) -1 piperazinylcarbonyl) pentyl, group 6- (4- (4-triflu oromethylbenzyl) -1 piperazinylcarbonyl) hexyl, group 4- (4-biphenylylmethyl) -1-piperazinylcarbonylmethyl, group 2- (4- (4-biphenyl imyl) 1) -1 -piperazinylcarbonyl) ethyl, group 3- (4- (4-biphenyl imyl 1) -1 piperazinylcarbonyl) propyl, group 4- (4- (4-biphenyl imyl 1) -1 -piperazinylcarbonyl) butyl, group 5- (4- (4-biphenylylmethyl) -1-piperazinylcarbonyl) pentyl, group 6- (4- (4-biphenylylmethyl) -1 piperazinylcarbonyl) hexyl, group 2,4-dibenzyl-1-piperazinylcarbonylmethyl, group 4benzyloxycarbonyl-3 -benzyl-1-piperazinylcarbonylmethyl, 4-ethoxycarbonyl-2,6 dibenzyl-1-piperazinylcarbonyl methyl group or the like.

[0386] A phenylcarbamoyl C1-6 alkyl group that can have at least one unsubstituted or halogen substituted C1-6 alkyl group as a substituent on the phenyl ring includes a phenylcarbamoyl C1-6 alkyl group which can have 1 to 3 alkyl groups C1-6 unsubstituted or substituted by halogen as a substituent on the phenyl ring, for example, a 4-methylphenylcarbamoylmethyl group, 2,4dimethylphenylcarbamoylmethyl group, 2,4,6-tnmethylphenylcarbamoylmethyl group, 3ethylphenylcarbamoylmethyl group, 2-n-propylmethylcarbon group 4-nbutilphenylcarbamoylmethyl, group 4-n-pentylphenylcarbamoylmethyl, group4-nhexylphenylcarbamoylmethyl, group 4-tnfluoromethylphenylcarbamoylmethyl, group2- (4trifluoromethylphenylcarbamoyl) ethyl, group 3- (3,5) - (4

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298/854 trifluoromethylphenylcarbamoyl) pentyl, group 6- (4-trifluoromethylphenylcarbamoyl) hexyl or the like.

[0387] Examples of a benzoxazolyl C1-6 alkyl group (which may have at least one oxo group as a substituent on the benzoxazole ring) include a benzoxazol-2-ylmethyl group, benzoxazol-4-ylmethyl group, benzoxazol-5-ylmethyl group , benzoxazol-6-ylmethyl group, benzoxazol-7-ylmethyl group, 2- (benzoxazol-2-yl) ethyl, group 1 (benzoxazol-4-yl) ethyl, group 3- (benzoxazol-5-yl) propyl, group 4- (benzoxazol-6yl) butyl, group 5- (benzoxazol-7-yl) pentyl, group 6- (benzoxazol-2-yl) hexyl, group 2methyl-3- (benzoxazol-4-yl) propyl, group 1, 1-dimethyl-2- (benzoxazol-5-yl) ethyl, (2,3-dihydro-2-oxo-benzoxazol-3-yl) methyl group, (2,3-dihydro-2-oxo-benzoxazol-4-yl group ) methyl, (2,3-dihydro-2-oxo-benzoxazol-5-yl) methyl group, (2,3-dihydro-2-oxo-benzoxazol-6yl) methyl, group (2,3-dihydro-2 -oxo-benzoxazol-7-yl) methyl group or the like.

[0388] A phenylthiocarbamoyl group that can be substituted on the phenyl ring by at least one halogen atom as a substituent includes a phenylthiocarbamoyl group that can be substituted on the phenyl ring by 1 to 5 halogen atoms as a substituent, for example, a phenylthiocarbamoyl group, 4fluorophenylthiocarbamoyl group, 4-chlorophenylthiocarbamoyl group, 4bromophenylthiocarbamoyl group, 3,4-dichlorophenylthiocarbamoyl group, 3,4,6trichlorophenylthiocarbamoyl group, 2,3,4,5,6-pentafluofylamyl group.

[0389] Examples of a C1-e alkoxycarbonyl group include a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, npentyloxycarbonyl group, n-hexyloxycarbonyl group, n-heptyloxycarbonyl group, noctiloxycarbonyl group or the like.

[0390] A C1-6 phenyl alkoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a halogen atom, Ci-e alkoxycarbonyl group, amino group which may have a C1 alkoxycarbonyl group -6 as a substituent, C1-6 alkyl group unsubstituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen, nitro group and C1-6 alkyl group includes a phenyl C1-6 alkoxycarbonyl group (which may substituted on the phenyl ring by 1 to 5, preferably 1 to 3 groups

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299/854 selected from a group consisting of a halogen atom, C1-6 alkoxycarbonyl group, amino group that may have a C1-6 alkoxycarbonyl group as a substituent, C1-6 alkyl group unsubstituted or substituted by halogen, alkoxy group C1-6 unsubstituted or substituted by halogen, nitro group and C1-6 alkylthio group), for example, a benzyloxycarbonyl group, 1-phenethyloxyoxycarbonyl group, 2-phenethyloxyoxycarbonyl group, 3-phenylpropoxycarbonyl group, 2-phenylpropoxycarbonyl group, 4-phenylbutoxycarbonyl group, 5-phenylpentyloxycarbonyl group, 4-phenylpentyloxycarbonyl group, 6-phenylexyloxycarbonyl group,

group 2-fluorobenzyloxycarbonyl, group 3-fluorobenzyloxycarbonyl, group 4- fluorobenzyloxycarbonyl, group 2-chlorobenzyloxycarbonyl, group 3- chlorobenzyloxycarbonyl, group 4-chlorobenzyloxycarbonyl, group 2- bromobenzyloxycarbonyl, group 3-bromobenzyloxycarbonyl, group 4- bromobenzyloxycarbonyl, group 2-iodobenzyloxycarbonyl, group 3- iodobenzyloxycarbonyl, group 4-iodobenzyloxycarbonyl, group 2.3- difluorobenzyloxycarbonyl, group 3,4-difluorobenzyloxycarbonyl, group 3.5- difluorobenzyloxycarbonyl, group 2,4-difluorobenzyloxycarbonyl, group 2.6- difluorobenzyloxycarbonyl, 2,4,6-trifluorobenzyloxycarbonyl group, group 2,3,4 , 5.6- pentafluorobenzyloxycarbonyl, group 3,4,5-trifluorobenzyloxycarbonyl, group 2.3- dichlorobenzyloxycarbonyl, group 3,4-dichlorobenzyloxycarbonyl, group 3.5- dichlorobenzyloxycarbonyl, group 2,4-dichlorobenzyloxycarbonyl, group 2.6- dichlorobenzyloxycarbonyl, group 2,4,6-trichlorobenzyloxycarbonyl, group 3 , 4.5- trichlorobenzyloxycarbonyl, group 2-trifluoromethylbenzyloxycarbonyl, group 3- methylbenzyloxycarbonyl, group 2,4-dimethylbenzyloxycarbonyl, group 2 , 4.6- trimethylbenzyloxycarbonyl, group 3-difluoromethylbenzyloxycarbonyl, group 4-

difluoromethylbenzyloxycarbonyl, 4-chloro-3-difluoromethylbenzyloxycarbonyl group, group

3-chloro-4-difluoromethylbenzyloxycarbonyl, 3-bromo-4-difluoromethylbenzyloxycarbonyl group, 3,5-difluoro-4-difluoromethylbenzyloxycarbonyl group, 3,5-ditrifluoromethylbenzyloxycarbonyl group, 3-trifluoromethylbenzyloxycarbonyl group, group 3-trifluoromethylbenzyloxycarbonyl group, group 3trifluoromethylbenzyloxycarbonyl, group 3-fluoro-4-trifluoromethylbenzyloxycarbonyl, group

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300/854

2-pentafluoroethylbenzyloxycarbonyl, group 4-chloro-3-pentafluoroethylbenzyloxycarbonyl, group 3-chloro-4-pentafluoroethylbenzyloxycarbonyl, group 2pentafluoroethylbenzyloxycarbonyl, bicarbonylmethyl, benzyloxycarbonyl trimethoxybenzyloxycarbonyl, 2trifluoromethoxybenzyloxycarbonyl group, 3-trifluoromethoxybenzyloxycarbonyl group, 4trifluoromethoxybenzyloxycarbonyl group, 4-fluoro-3-trifluoromethoxybenzyloxycarbonyl, 3-fluoro-4-trifluorooxycarbonyl group

4-pentafluoroethoxybenzyloxycarbonyl, group 3-chloro-4-trifluoromethoxybenzyloxycarbonyl, group 3-chloro-4-pentafluoroethoxybenzyloxycarbonyl, group 2- (2-trifluoromethylphenyl) ethoxycarbonyl, group 2- (3trifluoromethylphenyl) methylethoxy (2) group 2 (4-trifluoromethoxyphenyl) ethoxycarbonyl, 2- (2-pentafluoroethoxyphenyl) ethoxycarbonyl, group 2- (3-pentafluoroethoxyphenyl) ethoxycarbonyl, group 2- (4pentafluoroethoxyphenyl) ethoxycarbonyl, group 3- (2-trifluoroxymethylcarbonyl), group 3- 3-trifluoromethylphenyl) propoxycarbonyl, group 3- (4trifluoromethylphenyl) propoxycarbonyl, group 3- (2-trifluoromethylphenyl) propoxycarbonyl, group 3- (3-trifluoromethoxyphenyl) propoxycarbonyl (propyl) 3-propoxycarbonyl) (3- , group 3- (4-pentafluoroethoxyphenyl) propoxycarbonyl, group 4- (3pentafluoroethoxyphenyl) butoxycarbonyl, group 5- (4-trifluoromethylphenyl) pentyloxycarbonyl, group 4- (4-trifluoromethylphenyl) pentyloxic arbonyl, group 4- (4trifluoromethoxyphenyl) pentyloxycarbonyl, group 6- (3-trifluoromethylphenyl) hexyloxycarbonyl, group 6- (4-trifluoromethylphenyl) hexyloxycarbonyl, group 6- (4trifluoromethoxyphenyl) hexyloxycarbonyl, group 4-methylthioethyl , group 2- (2methylthiophenyl) ethoxycarbonyl, group 2- (3-methylthiophenyl) ethoxycarbonyl, group 2- (4methylthiophenyl) ethoxycarbonyl, group 3- (4-methylthiophenyl) propoxycarbonyl, group 4- (4methylthiophenyl) butoxycarbonyl, group 5- (4 -methyltiophenyl) pentyloxycarbonyl, group 6- (4Petition 870190039560, of 26/04/2019, p. 309/876

301/854 methylthiophenyl) hexyloxycarbonyl, 2-methoxycarbonylbenzyloxycarbonyl group, 3metoxicarbonylbenzyloxycarbonyl group, 4-methoxycarbonylbenzyloxycarbonyl group, group 2 (2-methoxycarbonylphenyl) ethoxycarbonyl, group 2- (3-methoxycarbonyl), group 2- (3-methoxycarbonyl), group 2- 3- (4-methoxycarbonylphenyl) propoxycarbonyl, group 4- (4-methoxycarbonylphenyl) butoxycarbonyl, group 5- (4-methoxycarbonylphenyl) pentyloxycarbonyl, group 6- (4-

methoxycarbonylphenyl) hexyloxycarbonyl, pentyloxycarbonylaminobenzyloxycarbonyl, ethoxycarbonylaminobenzyloxycarbonyl, group 4-n- group 4- group 4- propoxycarbonylaminobenzyloxycarbonyl, butoxycarbonylaminobenzyloxycarbonyl, group 4-ter- group 2- (n- hexyloxycarbonylaminophenyl) ethoxycarbonyl, butoxycarbonylaminophenyl) propoxycarbonyl, butoxycarbonylaminophenyl) butoxycarbonyl, butoxycarbonylaminophenyl) pentyloxycarbonyl, butoxycarbonylaminophenyl) hexyloxycarbonyl, group 3- (4-ter- group 4- (4-ter- group 5- (4-ter- group 6- (4-ter- group 2-nitrobenzyloxycarbonyl, group 3-

nitrobenzyloxycarbonyl, group 4-nitrobenzyloxycarbonyl, group 2- (2nitrophenyl) ethoxycarbonyl, group 2- (3-nitrophenyl) ethoxycarbonyl, group 2- (4nitrophenyl) ethoxycarbonyl, group 3- (2,4-dinitrophenyl) propoxycarbonyl, group 4- (4nitrophenyl) ) butoxycarbonyl, group 5- (4-nitrophenyl) pentyloxycarbonyl, group 6- (2,4,6trinitrophenyl) hexyloxycarbonyl, group 2-aminobenzyloxycarbonyl, group 3aminobenzyloxycarbonyl, group 4-aminobenzyloxycarbonyl, group 2- (2aminophenyl) 2- (ethoxycarbonyl), group 2- 2,3-diaminophenyl) ethoxycarbonyl, group 2- (4aminophenyl) ethoxycarbonyl, group 3- (2,4,6-triaminophenyl) propoxycarbonyl, group 4- (4aminophenyl) butoxycarbonyl, group 5- (4-aminophenyl) pentyloxycarbonyl, group 6 - (4aminophenyl) hexyloxycarbonyl, group 2-ethoxycarbonylbenzyloxycarbonyl, group 3 ethoxycarbonylbenzyloxycarbonyl, group 4-methoxycarbonylbenzyloxycarbonyl, group 2- (2etoxicarbonylphenyl) ethoxycarbonyl, group 2- (3-ethoxycarbonylphenyl) ethoxy (3) group (4-n-butox icarbonylphenyl) propoxycarbonyl, group 4- (4-n-pentyloxycarbonylphenyl) butoxycarbonyl, group 5- (4-nPetition 870190039560, from 26/04/2019, p. 310/876

302/854 hexyloxycarbonylphenyl) pentyloxycarbonyl, group 6- (4-netoxicarbonylphenyl) hexyloxycarbonyl or the like.

[0391] A benzhydryloxycarbonyl group (which can be substituted on the phenyl ring by at least one halogen atom) includes a benzhydryloxycarbonyl group (which can be replaced on the phenyl ring by 1 to 4 halogen atoms), for example, a benzhydryloxycarbonyl group , 3-fluorobenzhydryloxycarbonyl group, 4fluorobenzhydryloxycarbonyl group, 3,3'-difluorobenzhydryloxycarbonyl group, 3,4'-difluorobenzhydryloxycarbonyl group, 4,4'-difluorobenzhydryloxycarbonyl group, 3,4,4'trifluorobenzhydryloxycarbonyl group, group 3,4 '-tetrafluorobenzhydryloxycarbonyl, group 2,2', 4,4'-tetrafluorobenzhydryloxycarbonyl, group 3,3 ', 5,5'tetrafluorobenzhydryloxycarbonyl, group 3-chlorobenzhydryloxycarbonyl, group 4chlorobenzhydryloxycarbonyl, group 3,3'-dichlorohydryl dichlorobenzhydryloxycarbonyl, group 4,4'-dichlorobenzhydryloxycarbonyl, group 3,4,4'trichlorobenzhydryloxycarbonyl, group 3,3 ', 4,4'-tetrachlorobenzhydryloxycarbonyl, group 2,2', 4,4'-tetrachlorobenzhydryloxycarbyl onila, group 3,3 ', 5,5'-tetrachlorobenzhydryloxycarbonyl or similar.

[0392] Examples of a phenyl C1-6 alkoxycarbonyl group unsubstituted or substituted by phenyl include a benzyloxycarbonyl group, 1-phenylethoxycarbonyl group, 2-phenylethoxycarbonyl group, 3-phenylethoxycarbonyl group, 2-phenylpropoxycarbonyl group, 4-phenylbutoxycarbonyl group, group 5 -phenylpentoxicarbonyl, group 4phenylpentoxicarbonyl, group 6-phenylexyloxycarbonyl, group 2-biphenylylmethoxycarbonyl, group 2- (2-biphenylyl) ethoxycarbonyl, group 3- (2-biphenylyl) propoxycarbonyl, group 4- (2-

biphenylyl) butoxycarbonyl, group 5- (2-biphenylyl) pentoxycarbonyl, group 6- (2- biphenylyl) hexyloxycarbonyl, group 3-biphenylylmethoxycarbonyl, group 2- (3- biphenylyl) ethoxycarbonyl, group 3- (3-biphenylyl) propoxycarbonyl, group 4- (3- biphenylyl) butoxycarbonyl, group 5- (3-biphenylyl) pentoxycarbonyl, group 6- (3- biphenylyl) hexyloxycarbonyl, group 4-biphenylylmethoxycarbonyl, group 2- (4- biphenylyl) ethoxycarbonyl, group 3- (4-biphenylyl) propoxycarbonyl, group 4- (4- biphenylyl) butoxycarbonyl, group 5- (4-biphenylyl) pentoxycarbonyl, group 6- (4-

biphenylyl) hexyloxycarbonyl or the like.

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303/854 [0393] Examples of a C1-6 pyridyl alkoxycarbonyl group include a 2pyridylmethoxycarbonyl group, 3-pyridylmethoxycarbonyl group, 4-pyridylmethoxycarbonyl group,

group 2- (2-pihdil) ethoxycarbonyl, group 2- (3-pyridyl) ethoxycarbonyl, group 2- (4- pihdil) ethoxycarbonyl, group 3- (2-pihdil) propoxycarbonyl, group 3- (3- pihdil) propoxycarbonyl, group 3- (4-pihdil) propoxycarbonyl, group 4- (2- pihdil) butoxycarbonyl, group 4- (3-pyridyl) butoxycarbonyl, group 4- (4- pihdil) butoxycarbonyl, group 5- (2-pyridyl) pentyloxycarbonyl, group 5- (3- pyridyl) pentyloxycarbonyl, group 5- (4-pihdil) pentyloxycarbonyl, group 6- (2- pyridyl) hexyloxycarbonyl, group 6- (3-pihdil) hexyloxycarbonyl, group 6- (4- pihdil) hexyloxycarbonyl or the like. [0394] Examples of a group substituted C1-6 alkoxycarbonyl by alkox i Cl-6

include a methoxymethoxycarbonyl group, methoxyethoxycarbonyl group, 1ethoxyethoxycarbonyl group, n-propoxymethoxycarbonyl group, n-butoxymethoxycarbonyl group, n-pentyloxymethoxycarbonyl group, n-hexyloxymethoxycarbonyl group, 2-ethoxyoxycarbonyl group, 2-ethoxyethoxycarbonyl group, propyl group , n-pentyloxymethoxycarbonyl group, nhexyloxymethoxycarbonyl group, 3-methoxypropoxycarbonyl group, 4metoxybutoxycarbonyl group, 5-methoxypentyloxycarbonyl group, 6methoxyxyoxycarbonyl group or the like.

[0395] A C1-6 alkoxycarbonyl piperazinyl group (which can be substituted on the piperazine ring by at least one group selected from a group consisting of a C1-6 alkoxycarbonyl group and a phenyl C1-6 alkoxycarbonyl group that can be substituted by minus one halogen atom on the phenyl ring, as a substituent) includes a C1-6 alkoxycarbonyl piperazinyl group (which can be substituted on the piperazine ring by 1 to 3 groups selected from a group consisting of a C1-6 alkoxycarbonyl group and one C1-6 alkoxycarbonyl phenyl group which may have a 1 to 5 halogen atom in the phenyl ring, as a substituent), for example, a (1-piperazinyl) methoxycarbonyl group, group 2- (2piperazinyl) ethoxycarbonyl, group 1- (3-piperazinyl) ethoxycarbonyl, group 3- (4piperazinyl) propoxycarbonyl, group 4- (1-piperazinyl) butoxycarbonyl, group 5- (2

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304/854 piperazinyl) pentyloxycarbonyl, group 6- (3-piperazinyl) hexyloxycarbonyl, group 2-methyl-3 (1-piperazinyl) propoxycarbonyl, group 1,1-dimethyl-2- (4-piperazinyl) ethoxycarbonyl, group 2- ( 1-piperazinyl) ethoxycarbonyl, group 2- (4-methoxycarbonyl-1-piperazinyl) ethoxycarbonyl, group 2- (4-ethoxycarbonyl-1-piperazinyl) ethoxycarbonyl, group 2- (4-n-propoxycarbonyl-1piperazinyl) ethoxycarbonyl, group 2 - (4-ter-butopoxycarbonyl-1-piperazinyl) ethoxycarbonyl, group 2- (4-sec-butopoxycarbonyl-1-piperazinyl) ethoxycarbonyl, group 2- (4-npentyloxycarbonyl-1-piperazinyl) ethoxycarbonyl, group 2- (4- n-hexyloxycarbonyl-1 piperazinyl) ethoxycarbonyl, group 2- (4-benzyloxycarbonyl-1-piperazinyl) ethoxycarbonyl, group 2- (4-phenylethoxycarbonyl-1-piperazinyl) ethoxycarbonyl, group 2- (4- (3-phenylpropoxycarbonyl-1-piperazinyl) ethoxycarbonyl, group 2- (4- (2-fluorobenzyloxycarbonyl-

1-piperazinyl) ethoxycarbonyl, group 2- (4- (4-fluorobenzyloxycarbonyl-1- piperazinyl) ethoxycarbonyl, group 2- (4- (4-chlorobenzyloxycarbonyl-1- piperazinyl) ethoxycarbonyl, group 2- (4- (3-chlorobenzyloxycarbonyl-1- piperazinyl) ethoxycarbonyl, group 2- (4- (2-bromobenzyloxycarbonyl-1- piperazinyl) ethoxycarbonyl, group 2- (4- (2-chlorobenzyloxycarbonyl-1- piperazinyl) ethoxycarbonyl, group 2- (4- (3,4-difluorobenzyloxycarbonyl-1- piperazinyl) ethoxycarbonyl, group 2- (4- (2,3,4,5,6-pentafluorobenzyloxycarbonyl-1 - piperazinyl) methoxycarbonyl, group 2- (4- (2,4-dichlorobenzyloxycarbonyl-1- piperazinyl) ethoxycarbonyl, group 2- (4- (2,4,6-trichlorobenzyloxycarbonyl-1-

piperazinyl) ethoxycarbonyl, (3,4-methoxycarbonyl-1-piperazinyl) toxicarbonyl group, (2,5-methoxycarbonyl-4-benzyloxycarbonyl-1-piperazinyl) methoxycarbonyl group or the like. [0396] A phenoxycarbonyl group (which can be substituted on the phenyl ring by at least one group selected from a group consisting of a C1-6 alkyl group and a C1-6 alkoxy group) includes a phenoxycarbonyl group (which can be substituted on the ring phenyl by 1 to 3 groups selected from a group consisting of a C1-6 alkyl group and a C1-6 alkoxy group), for example, a phenoxycarbonyl group, 2-methylphenoxycarbonyl group, 3-methylphenoxycarbonyl group, 4-methylphenoxycarbonyl group, 2-ethylphenoxycarbonyl group, 3-ethylphenoxycarbonyl group, 4-ethylphenoxycarbonyl group, 4-propylphenoxycarbonyl group, 4-ter-butylphenoxycarbonyl group, 4butylphenoxycarbonyl group, 2,3-dimethylphenoxycarbonyl group, group 3,4,5

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305/854 trimethylphenoxycarbonyl, group 4-pentylphenoxycarbonyl, group 4-hexylphenoxycarbonyl, group 2-methoxyphenoxycarbonyl, group 3-methoxyphenoxycarbonyl, group 4 methoxyphenoxycarbonyl, group 2-ethoxyphenoxycarbonyl, group 4-ethoxyphenoxycarbonyl 4-terbutoxyphenoxycarbonyl, group 4-n-butoxyphenoxycarbonyl, group 2,3dimethoxyphenoxycarbonyl, group 3,4,5-trimethoxyphenoxycarbonyl, group 4pentoxyphenoxycarbonyl, group 4-hexyloxyphenoxycarbonyl, group 2-methyl-4methoxyphenoxycarbonyl or similar.

[0397] A benzoyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group) includes a benzoyl group (which can be substituted on the phenyl ring by 1 to 3 C1 alkyl groups -6 unsubstituted or substituted by halogen), for example, a benzoyl group, 2-methylbenzoyl group, 3-methylbenzoyl group, 4-methylbenzoyl group, 2-ethylbenzoyl group, 3-ethylbenzoyl group, 4-ethylbenzoyl group, 4-n- group propylbenzoyl, 4-terbutylbenzoyl group, 4-n-pentylbenzoyl group, 4-n-hexylbenzoyl group, 2,3dimethylbenzoyl group, 3,4-dimethylbenzoyl group, 2,4,6-trimethylbenzoyl group, 2trifluoromethylbenzyl group, 3-trifluoryl group 4-trifluoromethylbenzoyl group, 4-pentafluoroethylbenzoyl group, 2,3-difluoromethylbenzoyl group, 3,4trifluoromethylbenzoyl group or the like.

[0398] A C2-6 phenyl alkanoyl group (which can be substituted on the phenyl ring by at least one unsubstituted or halogen substituted C1-6 alkyl group) includes a C2-6 phenyl alkanoyl group (which can be substituted on the phenyl ring with 1 to 3 C1-6 alkyl groups not substituted or substituted by halogen), for example, a phenylacetyl group, 3-phenylpropionyl group, 4-phenylbutyryl group, 5-phenylpentanoyl group, 6-phenylexanoyl group, 2-methylphenylacetyl group, 3-methylphenylacetyl group, 4methylphenylacetyl group, 2-trifluoromethylphenylacetyl group, 3-trifluoromethylphenylacetyl group, 4-trifluoromethylphenylacetyl group, 3- (2,4-dimethylphenyl) propionyl group, group (2,4,6trimethylphenyl -methylphenyl) propionyl, group 3- (3-methylphenyl) propionyl, group 3- (4-methylphenyl) propionyl, group 3- (2-trifluoromethylphenyl) propionyl, group 3- (3trifluoromethylphenyl) propionyl, group 3- (4-trifluoromethylphenyl) ) propionyl, group 3- (3.5

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306/854 dimethylphenyl) propionyl, group 4- (4-trifluoromethylphenyl) butyryl, group 5- (4-trifluoromethylphenyl) pentanoyl, group 6- (3,5-ditrifluoromethylphenyl) hexanoyl, group 4- (4trifluoromethylphenyl) butyryl, group 5- (4 -pentafluoroethylphenyl) pentanoyl, group 6- (4pentafluoroethylphenyl) hexanoyl or the like.

[0399] Examples of C2-6 alkanoyl phenoxy group (which can be substituted on the phenyl ring by 1 to 3 halogen atoms) include a phenoxyacetyl group, 3-phenoxypropionyl group, 4-phenoxypropionyl group, 5-phenoxypropionyl group, 6-phenoxypropionyl group, group 4- (4-chlorophenoxy) butyryl, group 5- (4-chlorophenoxy) pentanoyl, group 6- (4-chlorophenoxy) hexanoyl, group 2-fluorophenoxyacetyl, group 3 fluorophenoxyacetyl, group 4-fluorophenoxyacetyl, group 2-chlorophenoxyacetyl, group 3cl group 4-chlorophenoxyacetyl, group 4-bromophenoxyacetyl, group 2,3-

difluorophenoxyacetyl, group 2-fluoro-4-chlorophenoxyacetyl, group 3.5- difluorophenoxyacetyl, group 2,4,6-trichlorophenoxyacetyl, group 3- (2- fluorophenoxy) propionyl, group 3- (3-fluorophenoxy) propionyl, group 3- (4- fluorophenoxy) propionyl, group 3- (2-chlorophenoxy) propionyl, group 3- (3- chlorophenoxy) propionyl, group 3- (4-chlorophenoxy) propionyl, group 3- (4- bromophenoxy) propionyl, group 3- (2,3-difluorophenoxy) propionyl, group 3- (2-fluoro-4- chlorophenoxy) propionyl, group 3- (3,5-difluorophenoxy) propionyl, group 4- (4- fluorophenoxy) butyryl, group 5- (4-boromophenoxy) pentanoyl, group 6- (4- chlorophenoxy) hexanoyl, group 4- (4-chlorophenoxy) butyryl, group 5- (4-

iodophenoxy) pentanoyl, group 6- (4-chlorophenoxy) hexanoyl or the like.

[0400] A C2-6 alkanoyl piperazinyl group (which may be substituted on the piperazine ring by at least one group selected from a group consisting of a C1-6 alkanoyl group; phenyl C1-6 alkyl group which may have on the phenyl ring by minus one, group as a substituent, selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen; a phenyl C1- alkoxycarbonyl group 6 which may have at least one group on the phenyl ring, as a substituent, selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group

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307/854 not substituted or substituted by halogen; phenylcarbamoyl C1-6 alkyl group that may have at least one group on the phenyl ring, as a substituent, selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group not replaced or replaced with halogen; phenylcarbamoyl which may have at least one group on the phenyl ring, as a substituent, selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group and unsubstituted or substituted C1-6 alkoxy group halogen; and benzoxazolyl group) includes a C2-6 alkanoyl piperazinyl group (which can be substituted on the piperazine ring by 1 to 3 groups selected from a group consisting of a C1e alkanoyl group; phenyl C1-6 alkyl group which may present on the phenyl ring from 1 to 5, preferably from 1 to 3 groups, as a substituent, selected from a group consisting of a halogen atom, unsubstituted or substituted C1-6 alkyl group and unsubstituted or substituted C1-6 alkoxy group halogen; a phenyl C 1-6 alkoxycarbonyl group which may present on the phenyl ring from 1 to 5, preferably from 1 to 3 groups, as a substituent, selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen; phenylcarbamoyl C1-6 alkyl group which may present in the phenyl ring from 1 to 5, preferably from 1 to 3 groups, as a substitut te, selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen; phenylcarbamoyl which may present on the phenyl ring from 1 to 5, preferably from 1 to 3 groups, as a substituent, selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and a group C1-6 alkoxy unsubstituted or substituted by halogen; and benzoxazolyl group), for example, a 1-piperazinylacetyl group, 3- (2-piperazinyl) propanoyl group, 4- (3piperazinyl) butyryl group, 4- (4-piperazinyl) pentanoyl group, 5- (1piperazinyl) pentaneyl group, group 6- (2-piperazinyl) hexanoyl, group 4-acetyl-1piperazinylacetyl, group 3- (4-propionyl-1-piperazinyl) propionyl, group 3- (4-butyryl-1) Petition 870190039560, of 26/04/2019, page 316/876

308/854 piperazinyl) butyryl, group 4- (4-pentanoyl-1-piperazinyl) butyryl, group 5- (4-hexanoyl-1piperazinyl) pentanoyl, group 6- (4-acetyl-1-piperazinyl) hexanoyl, group 4- benzyl-1piperazinylacetyl, group 3 - [(4- (2-phenyethyl) -1-piperazinyl] propionyl, group (4-acetyl-3-benzyl-1-piperazinyl) acetyl, group (4-benzyloxycarbonyl-2-benzyl-1-piperazinyl ) acetyl, group (4-phenylcarbamoyl-2,6-dibenzyl-1-piperazinyl) acetyl, group 4- [4- (1-phenylethyl) -1piperazinyl] butyryl, group [4- (3-phenylpropyl) -1-piperazinyl ] butyryl, group 5- [4- (5-phenyl Ipenti 1) -1-piperazinyl] pentanoyl, group 6- [4- (6-phenyl lexi 1) -1 -piperazinyl] hexanoyl, group 4- (4-phenylbenzyl ) -1-piperazinylacetyl, group 3- [4- (3-fluorobenzyl) -1piperazin l] propionyl, group 4- [4- (2,3,4,5,6-pentafluorobenzyl) -1 -piperazin l] butiri la, group 4- [4- (2,4-dichlorobenzyl) -1-piperazinyl] butyryl, group 5- [4- (2,4,6-trichlorobenzyl) -1piperazinyl] pentanoyl, group 6- [4- (4 -methylbenzyl) -1-piperazinyl] hexanoyl, group [4- (4trifluoromethylbenzyl ) -1-piperazinyl] acetyl, group [4- (3,5-ditrifluoromethylbenzyl 1) -1 piperazinyl] acetyl, group [4- (2,3-dimethylbenzyl) -1-piperazinyl] acetyl, group [4 - (2,4,6 trimethyl Ibenzi 1) -1-piperazinyl] acetyl, group 6- [4- (4-methoxybenzyl) -1 piperazinyl] hexanoyl, group [4- (4-trifluoromethoxybenzyl) -1-piperazinyl ] acetyl, group [4 (3,5-ditrifluoromethoxybenzyl) -1-piperazinyl] acetyl, group [4- (2,3-dimethoxybenzyl) -1 piperazinyl] acetyl, group [4- (2,4,6-trimethoxybenzyl ) -1-piperazinyl] acetyl, group 3- (4benzyloxycarbonyl-1-piperazinyl) propionyl, group 4- (2,4-dichlorobenzyloxycarbonyl-1 piperazinyl) acetyl, group 3- (4-benzyloxycarbonyl-1-piperazinyl) butyryl, group 4- (4-benzyloxycarbonyl-1-piperazinyl) butyryl, group 5- (4-benzyloxycarbonyl-1 piperazinyl) pentanoyl, group 6- (4-benzyloxycarbonyl-1-piperazinyl) hexanoyl, group 3 (4- (2 -fluorobenzyloxycarbonyl) -1-piperazinyl) propionyl, group 3- (4- (2-fluorobenzyloxycarbonyl) -1 -piperazinyl) butyryl, group 4- (4- (2-fluorobenzyloxycarbonyl) -1 p iperazini l) butiri la, group 5- (4- (2,3,4,5,6-pentafluorobenzyloxycarbonyl) -1 piperazinyl) pentanoyl, group 6- (4-fluorobenzyloxycarbonyl) -1-piperazinyl) hexanoyl, group 3- ( 4- (2,3-difluorobenzyloxycarbonyl-1-piperazinyl) butyryl, group 4- (4- (3fluorobenzyloxycarbonyl-1-piperazinyl) butyryl, group 5- (4- (3-fluorobenzyloxycarbonyl-1 piperazinyl) pentanoyl, group 3- ( 4- (4-fluorobenzyloxycarbonyl-1-piperazinyl) butyryl, group 4- (4- (4-fluorobenzyloxycarbonyl-1-piperazinyl) butyryl, group 5- (4- (4fluorobenzyloxycarbonyl) -1-piperazinyl) pentanoyl, group 6 - (4- (4Petition 870190039560, of 26/04/2019, p. 317/876

309/854 fluorobenzyloxycarboni 1) -1-piperazinyl) hexanoyl, group 3- (4- (2-chlorobenzyloxycarbonyl) 1 -piperazinyl) propionyl, group 3- (4- (2-chlorobenzyloxycarbonyl) -1 -piperazinyl) butyryl, group 4- (4- (2-chlorobenzyloxycarbonyl) -1-piperazinyl) butyryl, group 5- (4- (2chlorobenzyloxycarbonyl) -1 -piperazinyl) pentanoyl, group 6- (2,4,6trichlorobenzyloxycarbonyl) -1 - piperazinyl) hexanoyl, group 3- (4- (3-chlorobenzyloxycarbonyl) -1-piperazinyl) propionyl, group 3- (4- (3-chlorobenzyloxycarbonyl) 1-piperazinyl) butyryl, group 4- (4- (3-chlorobenzyloxycarbonyl) -1 -piperazinyl) butyryl, group 5- (4- (3-chlorobenzyloxycarbonyl) -1 -piperazinyl) pentanoyl, group 6- (3chlorobenzyloxycarbonyl-1-piperazinyl) hexanoyl, group 2- (4- (4-chlorobenzyloxycarbonyl) -1 piperazinyl) propionyl, group 3- (4- (4-chlorobenzyloxycarbonyl) -1-piperazinyl) butyryl, group 4- (4- (4-chlorobenzyloxycarbonyl) -1 -piperazinyl) butyril, group 5- (4- (4-chlorobenzyloxycarbonyl) - 1-piperazinyl) pentanoyl, group 6- (4-chlorobenzyloxycarbonyl-1 pip erazinyl) hexanoyl, group (4- (2-methylbenzyloxycarbonyl) -1-piperazinyl) acetyl, group (4- (2,4-dimethylbenzyloxycarbonyl) -1-piperazinyl) acetyl, group (4- (2,4,6 trimethylbenzyloxycarbonyl) -1-piperazinyl) acetyl, group 4- (2-methoxybenzyloxycarbonyl) -1 piperazinyl) acetyl, group (4- (2,4-dimethoxybenzyloxycarbonyl) -1-piperazinyl) acetyl, group (4- (2,4, 6-trimethoxybenzyloxycarbonyl) -1-piperazinyl) acetyl, ditrifluoromethylbenzyloxycarbonyl) -1-piperazinyl) acetyl group, ditrifluoromethoxybenzyloxycarbonyl) -1-piperazinyl) acetyl group, trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) -1-piperazinylpropyl butyril, trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) butyril, trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) pentanoyl group, trifluoromethylbenzyloxycarbonyl-1-piperazinyl) hexanoyl group, trifluoroxycarbonylmethyl) 1 -piperazin il) butiri la, gru po trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) pentanoyl, trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) butyril group, trifluoromethylbenzyloxycarbonyl) -1 -piperazinyl) butyril group, trifluoromethylbenzyloxycarbonyl group , 5 (4- (3,53- (4- (2-

3- (4- (2-

4- (4- (2-

5- (4- (2-

6- (4-

3- (4- (3-

4- (4- (3-

5- (4- (3-

3- (4- (4-

4- (4- (4-

5- (4- (4-

6- (4- (4-

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310/854 trifluoromethylbenzyloxycarbonyl) -1-piperazinyl) hexanoyl, tnfluoromethoxybenzyloxycarbonyl) -1-piperazinyl) propionyl group, trifluoromethoxybenzyloxycarbonyl) -1-piperazinyl) butinla, trifluoroxycarbonylmethyl) pentanoyl, tnfluoromethoxybenzyloxycarbonyl-1-piperazinyl) hexanoyl group, trifluoromethoxybenzyloxycarbonyl) -1-piperazinyl) butyryl group, trifluoromethoxybenzyloxycarbonyl) -1-piperazinyl) butinla, pentnyloxycarbonyl) piperazinyl) group

2- (4- (2-

3- (4- (2-

4- (4- (2-

5- (4- (2-

6- (43- (4- (3-

4- (4- (3-

5- (4- (3-

3- (4- (4-

4- (4- (4- trifluoromethoxybenzyloxycarbonyl) -1-piperazinyl) butyria, group 5- (4- (4 trifluoromethoxybenzyloxycarbonyl) -1 -piperazinyl) pentanoyl, group 6- (4- (4 trifluoromethoxybenzyloxycarbonyl) -1-piperazinyl ) hexanoyl, 4-phenylcarbamoylmethyl group

-piperazinylacetyl, group 3- (4-phenylcarbamoylmethyl-1-piperazinyl) propionyl, group 4- (4fluorophenylcarbamoylmethyl-1 -piperazin l) acetyl, group 3- (4- (2,3,4,5,6-

pentafluorophenylcarbamoylmethyl) -1-piperazinyl) propionyl, group chlorophenylcarbamoylmethyl-1-piperazinylacetyl, group dichlorophenylcarbamoylmethyl) -1-piperazin i l) propion ia, group methylphenylcarbamoylmethyl) -1-piperazinylacetyl, group dimethylphenylcarbamoylmethyl) -1-piperazin i l) propion ia, group methoxyphenylcarbamoylmethyl) -1-piperazinylacetyl, group trimethoxyphenylcarbamoylmethyl) -1-piperazin i l) propion ia, group trifluoromethylphenylcarbamoylmethyl) -1-piperazinyl) propionyl, group trifluoromethoxyphenylcarbamoylmethyl) -1-piperazinylacetyl, group 4- (4- 3- (4- (3,4- 4- (4- 3- (4- (2,4- 4- (43- (4- (2,4,63- (4- (4- 4- (4- 3- (4- (4-

trifluoromethoxyphenylcarbamoylmethyl) -1-piperazinyl) propionyl, group 4-phenylcarbamoyl-1 piperazinylacetyl, group 3- (4-phenylcarbamoyl-1-piperazinyl) propionyl, group 4- (4fluorophenylcarbamoyl-1-piperazinyl-3-piperazinac 3,4,5,6 pentafluorophenylcarbamoyl) -1-piperazinyl] propioniIa, group 4- (4-chlorophenylcarbamoyl-1 piperazinylacetyl, group 4- (2,4-dichlorophenylcarbamoyl-1-piperazinylacetyl, group 4- (2,6dichlorophenylcarbamoyl-1 piperazinylacetyl, group 3- (4- (4-chlorophenylcarbamoyl) -1 Petition 870190039560, of 26/04/2019, page 319/876

311/854 piperazinyl) propionyl, group 4- (4-methylphenylcarbamoyl-1-piperazinylacetyl, group 3- (4 (3,4-dimethylphenylcarbamoyl) -1 -piperazinyl) propionyl, group 4- (4-methoxyphenylcarbamoyl-1 piperazinylacetyl, group 3- [4- (2,4,6-trimethoxyphenylcarbamoyl) -1-piperazinyl] propionyl, group 3- (4- (4-trifluoromethylphenylcarbamoyl) -1-piperazinyl) propionyl, group 4- (3,5ditrifluoromethoxyphenylcarbamoyl) -1 - piperazin i lacetil, group 3- (4- (4trifluoromethoxyphenylcarbamoyl) -1-piperazinyl) propionyl, group 3- (4- (4fluorophenylcarbamoyl) -1 -piperazinyl) propionyl, group 3- (4- ( 4-methylphenylcarbamoyl) -1 piperazinyl) propionyl, group 3- (4- (4-methoxyphenylcarbamoyl) -1 -piperazinyl) propionyl, group 4- (2-benzoxazolinyl) -1-piperazinylacetyl, group 3- (4- (2-benzoxazolinyl) -1piperazinyl) propionyl, group 4- (4- (2-benzoxazolinyl) -1-piperazinyl) butyryl, group 5- (4 (2-benzoxazolinyl) -1-piperazinyl) pentanoyl, group 6 - (4- (2-benzoxazolinyl) -1 piperazinyl) hexanoyl or the like.

[0401] A phenylcarbamoyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of a halogen atom, an amino group which can have a C1-6 alkyl group as a substituent, carboxyl group, C1-6 alkoxycarbonyl group, C1-6 alkyl group unsubstituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen, piperazinyl group which may have a C1-6 alkyl group as a substituent on the piperazine ring and morpholino group ) includes a phenylcarbamoyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of a halogen atom, an amino group which can have 1 to 2 C1-6 alkyl groups as a substituent, group carboxyl, C1-6 alkoxycarbonyl group, C1-6 alkyl group unsubstituted or substituted by halogen, C1-6 alkoxy group unsubstituted or substituted by halogen, piperazinyl group that can present 1 to 3 C1-6 alkyl groups as a substituent on the piperazine ring and morpholone group, and an amino group moiety may be substituted by another C1-6 alkyl group or phenyl C1-6 alkyl group), for example, a phenylcarbamoyl group, 2-fluorophenylcarbamoyl, group 3fluorophenylcarbamoyl, group 4-fluorophenylcarbamoyl, group 2-chlorophenylcarbamoyl, group 3-chlorophenylcarbamoyl, group 4-chlorophenylcarbamoyl, group 2bromophenylcarbamoyl, group 3-b-group 3

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312/854

2-iodophenylcarbamoyl group, 3-iodophenylcarbamoyl group, group 4- iodophenylcarbamoyl, group 2,3-difluorophenylcarbamoyl, group 3.4- difluorophenylcarbamoyl, group 3,5-difluorophenylcarbamoyl, group 2.4- difluorophenylcarbamoyl, group 2,6-difluorophenylcarbamoyl, group 2.3- dichlorophenylcarbamoyl, group 3,4-dichlorophenylcarbamoyl, group 3.5- dichlorophenylcarbamoyl, group 2,4-dichlorophenylcarbamoyl, group 2.6- dichlorophenylcarbamoyl, group 3,4,5-trifluorophenylcarbamoyl, group 2.3- difluorophenylcarbamoyl, group 3,4,5-trichlorophenylcarbamoyl, group 2.4.6- trifluorophenylcarbamoyl, group 2,4,6-trichlorophenylcarbamoyl, group 2-

methylphenylcarbamoyl, 3-methylphenylcarbamoyl group, 4-methylphenylcarbamoyl group, 2-methyl-3-chlorophenylcarbamoyl group, 3-methyl-4-chlorophenylcarbamoyl group, 2-chloro-4-methylphenylcarbamoyl group, group 2-group 3-trifluoromethylphenylcarbamoyl, 4trifluoromethylphenylcarbamoyl group, N-methyl-N-phenylcarbamoyl group, N- (2-fluorophenyl) N-methylcarbamoyl group, N- (3-fluorophenyl) -N-methylcarbamoyl group -methylcarbamoyl, N- (2-chlorophenyl) -N-methylcarbamoyl group, N- (3-chlorophenyl) group -Nmethylcarbamoyl, N- (4-chlorophenyl) -N-methylcarbamoyl group, N- (4-bromophenyl) -Nmethylcarbamoyl group , N- (2-iodophenyl) -N-methylcarbamoyl group, N- (3-iodophenyl) -Nmethylcarbamoyl group, N- (4-iodophenyl) -N-methylcarbamoyl group, N- (2,3-difluorophenyl) N- group methylcarbamoyl, N- (3,4-difluorophenyl) -N-methylcarbamoyl group, N- (3,5-difluorophenyl) -N-methylcarbamoyl group, N- (2,4-difluorophenyl) -N-methylcarb group moíla, group N- (2,6-difluorophenyl) -N-methylcarbamoyl, group N- (2,3-dichlorophenyl) -N-methylcarbamoyl, group N- (3,4-dichlorophenyl) -N-methylcarbamoyl, group N- (3,5-dichlorophenyl) -Nmethylcarbamoyl, group N- (2,4-dichlorophenyl) -N-methylcarbamoyl, group N- (2,6dichlorophenyl) -N-methylcarbamoyl, group N- (3,4,5-trifluorophenyl) -N-methylcarbamoyl, group N- (3,4,5-trichlorophenyl) -N-methylcarbamoyl, group N- (2,4,6-trifluorophenyl) -Nmethylcarbamoyl, group N- (2,4,6-trichlorophenyl) - N-methylcarbamoyl, N- (2methylphenyl) -N-methylcarbamoyl group, N- (3-methylphenyl) -N-methylcarbamoyl group, N- (4methylphenyl) -N-methylcarbamoyl group, N- (2-methyl-3-chlorophenyl group) ) -N-methylcarbamoyl, group N- (3-methyl-4-chlorophenyl) -N-methylcarbamoyl, group N- (2-chloro-4-methylphenyl) -NPetition 870190039560, from 26/04/2019, p. 321/876

313/854 methylcarbamoyl, N- (2-methyl-3-fluorophenyl) -N-methylcarbamoyl group, N- (2trifluoromethylphenyl) -N-methylcarbamoyl group, N- (4-trifluoromethylphenyl) -Nmethylcarbamoyl group, N-group-N-group -phenylcarbamoyl, N-benzyl-N- (2-fluorophenyl) carbamoyl group, N-benzyl-N- (3-fluorophenyl) carbamoyl group, N-benzyl-N (4-fluorophenyl) carbamoyl group, N-benzyl-N- ( 2-chlorophenyl) carbamoyl, N-benzylN- (3-chlorophenyl) carbamoyl group, N-benzyl-N- (4-chlorophenyl) carbamoyl group, N-benzylN- (2-bromophenyl) carbamoyl group, N-benzyl-N group - (3-bromophenyl) carbamoyl, Nbenzyl-N- (4-bromophenyl) carbamoyl group, N-benzyl-N- (2-iodophenyl) carbamoyl group, N-benzyl-N- (3-iodophenyl) carbamoyl group, group N -benzyl-N- (4-iodophenyl) carbamoyl, group N-benzyl-N- (2,3-difluorophenyl) carbamoyl, group N-benzyl-N- (3,4difluorophenyl) carbamoyl, group N-benzyl-N- ( 3,5-difluorophenyl) carbamoyl, Nbenzyl-N- (2,4-difluorophenyl) carbamoyl group, N-benzyl-N- (2,6-difluorophenyl) carbamoyl group, N-benzyl-N- (2 , 3-dichlorophenyl) carbamoyl, N-benzyl-N- (3,4dichlorophenyl) carbamoyl group, N-benzyl-N- (3,5-dichlorophenyl) carbamoyl group, N-benzylN- (2,4-dichlorophenyl) carbamoyl group , N-benzyl-N- (2,6-dichlorophenyl) carbamoyl group, N-benzyl-N- (3,4,5-triifluorophenyl) carbamoyl group, N-benzyl-N- (3,4,5trichlorophenyl) carbamoyl group , N-benzyl-N- (2,3-difluorophenyl) carbamoyl group, Nbenzyl-N- (2,4,6-trichlorophenyl) carbamoyl group, N-benzyl-N- (2-methylphenyl) carbamoyl group, N- group benzyl-N- (3-methylphenyl) carbamoyl, N-benzyl-N- (4-methylphenyl) carbamoyl group, N-benzyl-N- (2-methyl-3-chlorophenyl) carbamoyl group, N-benzyl-N- group (3-methyl-4-chlorophenyl) carbamoyl, N-benzyl-N- (2-chloro-4-methylphenyl) carbamoyl group, Nbenzyl-N- (2-methyl-3-fluorophenyl) carbamoyl group, N-benzyl-N- group (2trifluoromethylphenyl) carbamoyl, N-benzyl-N- (3-trifluoromethylphenyl) carbamoyl group, N-benzyl-N- (4-trifluoromethylphenyl) carbamoyl group, 2-pentafluoroethylphenylcarbamoyl group, 3-pentafluoro carbamoyl group rupo 4-pentafluoroethylphenylcarbamoyl, 2-isopropylphenylcarbamoyl group, 3-isopropylphenylcarbamoyl group, 4isopropylphenylcarbamoyl group, 2-ter-butylphenylcarbamoyl group, 3-terbylphenylcarbamoyl group, 3-terbylphenylcarbamoyl group, 3-terbylphenylcarbamoyl group 4-secbutylphenylcarbamoyl, group 2-n-heptafluoropropylphenylcarbamoyl, group 3-n

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314/854 heptafluoropropiIfenilcarbamoíla group, 4-n-heptafluoropropilfenilcarbamoíla, 4pentilfenilcarbamoíla group, 4-hexilfenilcarbamoíla group, 2-metoxifenilcarbamoila group, 3-metoxifenilcarbamoíla group, 4-metoxifenilcarbamoíla group, 2-methoxy-3clorofenilcarbamoíla group, 2-fluoro-3-metoxifenilcarbamoíla group, 2-fluoro-4metoxifenilcarbamoíla, 2,6-dimetoxifenilcarbamoíla group, 2,3,4trifluorofenilcarbamoíla, 3,4,5-trifluorofenilcarbamoíla group, 2trifluorometoxifenilcarbamoíla group, 3-trifluorometoxifenilcarbamoíla, 4trifluorometoxifenilcarbamoíla group, 2-pentafluoroetoxifenilcarbamoíla group, 3pentafluoroetoxifenilcarbamoíla, group 4-pentafluoroetoxiphenylcarbamoyl, group 2isopropoxyphenylcarbamoyl, group 3-isopropoxyphenylcarbamoyl, group 4isopropoxyphenylcarbamoyl, group 2-ter-butoxyphenylcarbamoyl, group 3-terbutoxyphenylcarbamoyl-group, 3-group 4-group amoíla, 4-secbutoxifenilcarbamoíla group, 2-nheptafluoropropoxifenilcarbamoíla group, 3-nheptafluoropropoxifenilcarbamoíla, 4-nheptafluoropropoxifenilcarbamoíla group, 4-pentiloxifenilcarbamoíla group, 4-hexiloxifenilcarbamoíla group, 2dimetilaminofenilcarbamoíla, 2,4-dimetilaminofenilcarbamoíla group, 2,4 , 6trimetilaminofenilcarbamoíla group, 3-dimetilaminofenilcarbamoíla group, 4metilaminofenilcarbamoíla group, 2-carboxifenilcarbamoíla, 3carboxifenilcarbamoíla group, 4-carboxifenilcarbamoíla group, 2,3dicarboxifenilcarbamoíla, 2,4,6-tricarboxifenilcarbamoíla group, 2metoxicarbonilfenilcarbamoíla group, 3-metoxicarbonilfenilcarbamoíla group, 4metoxicarbonilfenilcarbamoíla group, 2-ethoxycarbonylphenylcarbamoyl, 3etoxicarbonylphenylcarbamoyl group, 4-ethoxycarbonylphenylcarbamoyl group, 2propoxycarbonylphenylcarbamoyl group, 3-propoxycarbonylphenylcarbamoyl group, 4propoxycarbonylphenylcarbamoyl group arbamoyl, group 2- (2,4dim ethyl 1-1-piperazinyl) phenylcarbamoyl, group 2- (2,3,4-trimethy 1-1 piperazinyl) phenylcarbamoyl, group 2- (4-methyl-1-piperazinyl) phenylcarbamoyl, group 3- (4m ethyl 1-1 -piperazinyl) phenylcarbamoyl, group 4- (4-methyl-1-piperazinyl) phenylcarbamoyl, group 2-morpholinophenylcarbamoyl, group 3-morpholinophenylcarbamoyl, group 4

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315/854 morpholinophenylcarbamoyl or similar.

[0402] A phenyl C1-6 alkylcarbamoyl group (which may be substituted on the phenyl ring by at least one group selected from a group consisting of an unsubstituted or substituted C1-6 alkyl group and an unsubstituted C1-6 alkoxy group or substituted by halogen) includes a phenyl C1-6 alkylcarbamoyl group (which can be substituted on the phenyl ring by 1 to 3 groups selected from a group consisting of an unsubstituted C1-6 alkyl group or substituted by halogen and C1 alkoxy group -6 unsubstituted or substituted by halogen), for example, a benzylcarbamoyl group, 1-phenylethylcarbamoyl group, 2-phenylethylcarbamoyl group, 3-phenylpropylcarbamoyl group, 4-phenylbutylcarbamoyl group, 5-phenylpentylcarbamoyl group, 6-phenylexylcarb group 3-phenylpropylcarbamoyl, group 1,1-dimethyl-2-phenylethylcarbamoyl, group 2-methylbenzylcarbamoyl, group 3-methylbenzylcarbamoyl, group 4-methylbenzylcarbamoyl, group 2,4-dimethyl ilbenzilcarbamoíla group, 2,4,6trimetilbenzilcarbamoíla group, 4-trifluoromethyl-3-metoxibenzilcarbamoíla, 2etilbenzilcarbamoíla group, 3-etilbenzilcarbamoíla group, 4-etilbenzilcarbamoíla group, 2-isopropilbenzilcarbamoíla group, 3-isopropilbenzilcarbamoíla group 4isopropilbenzilcarbamoíla group, 2,4-dimetoxibenzilcarbamoíla group, 2,4,6trimetoxibenzilcarbamoíla group, 4-trifluoromethoxy-3-metilbenzilcarbamoíla, 4metoxibenzilcarbamoíla group, 2-etoxibenzilcarbamoíla group, 3etoxibenzilcarbamoíla, 4-etoxibenzilcarbamoíla group, 2isopropoxibenzilcarbamoíla group, 3-isopropoxibenzilcarbamoíla, 4isopropoxibenzilcarbamoíla group, 4-tnfluorometilbenzilcarbamoíla group, 4pentafluoroethylbenzylcarbamoyl, group 4-n-heptafluoropropylbenzylcarbamoyl, group 4-trifluoromethoxybenzylcarbamoyl, group 4-pentafluoroethoxybenzylcarbamoyl, group 4n-heptafluoropropoxybenzylcarbamoyl or similar.

[0403] A piperazinylcarbonyl group (which can be substituted on the piperazine ring by at least one group selected from a group consisting of a C1-6 alkoxycarbonyl group, a C1-6 alkoxycarbonyl phenyl group that can have at least one C1- alkyl group 6 unsubstituted or substituted by halogen in the phenyl ring and phenyl C1-6 alkyl group which may have at least one C1-6 alkyl group

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316/854 unsubstituted or substituted by halogen on the phenyl ring) includes a piperazinylcarbonyl group (which can be substituted on the piperazine ring by 1 to 3 groups selected from a group consisting of a C1-6 alkoxycarbonyl group, a C1 phenyl alkoxycarbonyl group -6 which can have 1 to 3 C1-6 alkyl groups unsubstituted or substituted by halogen on the phenyl ring and phenyl C1-6 alkyl group which can have 1 to 3 C1-6 alkyl groups unsubstituted or substituted by halogen on the ring phenyl), for example, a 1-piperazinylcarbonyl group, 2piperazinylcarbonyl group, 3-piperazinylcarbonyl group, 4-piperazinylcarbonyl group, 4-ter-butoxycarbonyl-1-piperazinylcarbonyl group, group 4- (4-methylbenzyloxycarbonyl) -1 piperazinyl group - (2,4-dimethylbenzyloxycarbonyl) -1-piperazinylcarbonyl, group 4- (2,4,6-trimethylbenzyloxycarbonyl) -1 -piperazinylcarbonyl, group 4- (4trifluoromethylbenzyloxycarbonyl) -1 -piperazinylcarbonyl, group 4- (4-methyl benzyl) -1 piperazinylcarbonyl, group 4- (3,4-dimethylbenzyl) -1-piperazinylcarbonyl, group 4- (3,4,5trim eti Ibenzi l) -1 -piperazinylcarbonyl, group 4- (4-trifluoromethylbenzyl) -1 piperazinylcarbonyl , 4-methoxycarbonyl-3-benzyl-1-piperazinylcarbonyl group, 4-benzyloxycarbonyl-3,5-dimethoxycarbonyl-1-piperazinylcarbonyl group or the like.

[0404] A C1-6 phenyl alkoxy group (the phenyl group may have at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkoxy group, and a non-substituted C1-6 alkoxy group) substituted or substituted by halogen, as a substituent on the phenyl ring) is a C 1-6 phenyl alkoxy group that can be substituted by 1 to 5, preferably 1 to 3 groups selected from a group consisting of a halogen atom, C1-6 alkyl group unsubstituted or substituted by halogen and C1-6 alkoxy group unsubstituted or substituted by halogen, as defined above, examples of which include a benzyloxy group, 2-phenyloxy group, 3-phenylpropoxy group, 2-phenylpropoxy group, group 4-phenylbutoxy, 5-phenylpentoxy group, 4-phenylpentoxy group, 6-phenylexyloxy group, 2-fluorobenzyloxy group, 3-fluorobenzyloxy group, 4-fluorobenzyloxy group, 2- (2-fluorophenyl) ethoxy group, 2- (3-fluorophenyl) group il) ethoxy, 2- (4-fluorophenyl) ethoxy group, 2-chlorobenzyloxy group, 3-chlorobenzyloxy group, 4-chlorobenzyloxy group, 2-fluoro4-bromobenzyloxy group, 4-chloro-3-fluorobenzyloxy group, group 2,3, 4-trichlorobenzyloxy, group

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317/854

3.4.5- trifluorobenzyloxy, 2,3,4,5,6-pentafluorobenzyloxy group, 2,4,6trichlorobenzyloxy group, 4-isopropylbenzyloxy group, 4-n-butylbenzyloxy group, 4methylbenzyloxy group, 2-methylbenzyloxy group, 3-methylbenzyl group , 2,4dimethylbenzyloxy group, 2,3-dimethylbenzyloxy group, 2,6-dimethylbenzyloxy group, 3,5dimethylbenzyloxy group, 2,5-dimethylbenzyloxy group, 2,4,6-trimethylbenzyloxy group, 3,5di (trifluoromethyl) benzyloxy group, 4-isopropoxybenzyloxy group, 4-n-butoxybenzyloxy group, 4-methoxybenzyloxy group, 2-methoxybenzyloxy group, 3-methoxybenzyloxy group, 2,4dimethoxybenzyloxy group, 2,3-dimethoxybenzyloxy group, 2,6-dimethoxybenzyloxy group, 3,5dimethoxy group , 2,5-dimethoxybenzyloxy group, 2,4,6-trimethoxybenzyloxy group, group

3.5- di (trifluoromethoxy) benzyloxy, 2-isopropoxybenzyloxy group, 3-chloro-4-methoxybenzyloxy group, 2-chloro-4-trifluoromethoxybenzyloxy group, 3-methyl-4fluorobenzyloxy group, 4-bromo-3-trifluoroethyl group -chlorophenyl) ethoxy, group 2- (3-chlorophenyl) ethoxy, group 2- (4-chlorophenyl) ethoxy, group 2-trifluoromethylbenzyloxy,

3-trifluoromethylbenzyloxy group, 4-trifluoromethylbenzyloxy group, group 2- trifluoromethoxybenzyloxy, group 3-trifluoromethoxybenzyloxy, group 4- trifluoromethoxybenzyloxy, group 2- (2-trifluoromethylphenyl) ethoxy, group 2- (3- trifluoromethylphenyl) ethoxy, group 2- (4-trifluoromethylphenyl) ethoxy, group 2- (2- trifluoromethoxyphenyl) ethoxy, group 2- (3-trifluoromethoxyphenyl) ethoxy, group 2- (4- trifluoromethoxyphenyl) ethoxy, group 3- (2-trifluoromethylphenyl) propoxy, group 3- (3- trifluoromethylphenyl) propoxy, group 3- (4-trifluoromethylphenyl) propoxy, group 3- (2- trifluoromethylphenyl) propoxy, group 3- (3-trifluoromethoxyphenyl) propoxy, group 3- (4- trifluoromethoxyphenyl) propoxy, group 4- (3-trifluoromethylphenyl) butoxy, group 5- (4- trifluoromethylphenyl) pentoxy, group 4- (4-trifluoromethylphenyl) pentoxy, group 4- (4- trifluoromethoxyphenyl) pentoxy, group 6- (3-trifluoromethylphenyl) hexyloxy, group 6- (4-

trifluoromethylphenyl) hexyloxy, group 6- (4-trifluoromethoxyphenyl) hexyloxy or the like.

[0405] A C3-8 cycloalkyl group - C1-6 alkyl is a group consisting of a cyclic alkyl group having 3 to 8 carbon atoms and an alkyl group having 1 to 6 carbon atoms, examples of which are include a cyclopropylmethyl group, 2-cyclopropylethyl group, 3-cyclopropylpropyl group, 4cyclopropylbutyl group, 5-cyclopropylpentyl group, 6-cyclopropylexyl group, group

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318/854 cyclobutylmethyl, 2-cyclobutylethyl group, 3-cyclobutylpropyl group, 4-cyclobutylbutyl group, 5-cyclobutylpentyl group, 6-cyclobutylexyl group, cyclopentylmethyl group, 2-cyclopentylethyl group, 3-cyclopentylpropyl group, 4-cyclopentylbutyl group, group 5-cyclopentylbutyl, group 5 6-cyclopentylexyl, cyclohexylmethyl group, 2-cyclohexylethyl group, 3-cyclohexylpropyl group, 4-cyclohexylbutyl group, 5-cyclohexylpentyl group, 6-cyclohexylexyl group, cycloheptylmethyl group, 2-cyclohexylmethyl group, 2-cyclohexylmethyl group heptylethyl, group 3-cycloheptylpropyl, group 4-cycloheptylButyl, group 5-cycloheptylpentyl, group

6-cycloheptylhexyl, cyclooctylmethyl group, cyclooctyl propyl, 4-cyclooctylbutyl group, cyclooctylexyl or the like.

2-cyclooctylethyl group, 5-cyclooctylpentyl group, group group

36 [0406] The methods of producing those explained below.

Reaction scheme 1 compounds of the present invention are

H

I N) ^ X1

O ₂ NN o ₂ n (CH ₂ ) _n R ² (3a)

(2) [0407] where R ¹ , R ^{2 and} n are as indicated above, and Xi represents a halogen atom or nitro group.

[0408] According to reaction scheme 1, the compound of the present invention represented by the general formula (1a) is produced by reacting a 4nitroimidazole compound represented by the general formula (2) with an epoxy compound represented by the general formula (3a) in presence or absence of a basic compound to obtain a compound represented by the general formula (4a), and then subjecting the obtained compound to a ring closing reaction.

[0409] The molar ratio of the compound of general formula (2) to the compound of general formula (3a) can generally be between 1: 0.5 and 1: 5, and preferably between 1: 0.5 and 1: 3.

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319/854 [0410] Known compounds can be used widely as a basic compound here. Examples of a basic compound of the aforementioned type include basic inorganic compounds, such as a metal hydride, metal alcoholate, hydroxide, carbonate or hydrogen carbonate, and basic organic compounds, such as acetate.

[0411] Specific examples of a metal hydride include sodium hydride and potassium hydride. Specific examples of a metal alcoholate include sodium methoxide, sodium ethoxide and potassium tert-butoxide. Specific examples of a hydroxide include sodium hydroxide and potassium hydroxide. Specific examples of a carbonate include sodium carbonate and potassium carbonate. Specific examples of a hydrogen carbonate include sodium hydrogen carbonate and potassium hydrogen carbonate. In addition to the above compounds, it is also possible to include sodium amide and the like in basic inorganic compounds.

[0412] Specific examples of acetate include sodium acetate and potassium acetate. In addition to these compounds, specific examples of basic organic compounds include thethylamine, thmethylamine, diisopropylethylamine, pyridine, dimethylaniline, 1-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] noneno5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), and 1,4-diazabicyclo [2.2.2] octane (DABCO).

[0413] The molar ratio of the above basic compound to the compound of general formula (2) can generally be between 0.1: 1 and 2: 1, preferably between 0.1: 1 and 1: 1, and, more preferably, between 0.1: 1 and 0.5: 1.

[0414] The reaction of the compound of general formula (2) with the compound of general formula (3a) is generally carried out in an appropriate solvent.

[0415] Common solvents can be used widely as the solvent above, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type include polar aprotic solvents, such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) or acetonitrile, ketone solvents, such as acetone or methyl ethyl ketone, hydrocarbon solvents such as benzene, toluene, xylene, tetraline or liquid paraffin, alcohol solvents, such as methanol, ethanol, isopropanol, n-butanol or ter-butanol, solvents of

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320/854 ether, such as tetrahydrofuran (THF), dioxane, dipropyl ether, diethyl ether or diglyme, ester solvents, such as ethyl acetate or methyl acetate, and mixed solvents thereof. It is possible that water is contained in these solvents.

[0416] The reaction of the compound of general formula (2) with the compound of general formula (3a) is carried out, for example, as follows: The compound of general formula (2) is dissolved in a reaction solvent, and, while stirring, a basic compound is added to the mixture cooled on ice or to room temperature (30 ° C). Then, the mixture is stirred at room temperature at 80 ° C for 30 minutes to 1 hour, and the compound of general formula (3a) is then added to this. Then, the mixture is further stirred generally at a temperature between room temperature and 100 ° C, and preferably from 50 ° C to 80 ° C, generally for 30 minutes to 60 hours, and preferably for 1 to 50 hours.

[0417] The compound (2) used as a starting material is known. Compound (3a) includes an unprecedented compound, and a method for producing the compound will be explained later.

[0418] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, a compound of general formula (4a) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0419] The compound of the present invention represented by the general formula (1a) is produced by subjecting the compound represented by the general formula (4a) to a ring closing reaction. The ring closure reaction is carried out by dissolving the compound obtained above represented by the general formula (4a) in a reaction solvent and then adding a basic compound to this, followed by stirring.

[0420] Here, as a reaction solvent and a basic compound, it is possible to use the same reaction solvent and the same basic compound as used in the reaction above the compound of general formula (2) with the compound of general formula (3a) . [0421] The molar ratio of the basic compound to the compound of the general formula (4a)

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321/854 is generally equal to 1: 1 or greater, preferably between 1: 1 and 5: 1, and more preferably between 1: 1 and 2: 1.

[0422] The reaction temperature for the ring closure reaction is generally from 0 ° C to 150 ° C, preferably from room temperature to 120 ° C, and more preferably from 50 ° C to 100 ° C. The reaction time is generally from 30 minutes to 48 hours, preferably from 1 to 24 hours, and more preferably from 1 to 12 hours.

[0423] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound of general formula (1 a) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0424] In the present invention, the reaction mixture can be directly subjected to the following ring closure reaction without isolating the compound of general formula (4a) generated as a result of a reaction group of the compound of general formula (2) with compound of general formula (3a). For example, the compound of general formula (2) is reacted with the compound of general formula (3a) at room temperature up to 80 ° C, and then a basic compound is added to the reaction mixture obtained followed by stirring at 50 ° C. ° C to 100 ° C. Otherwise, after the compound of general formula (2) is reacted with the compound of general formula (3a) at room temperature up to 80 ° C, the reaction mixture obtained is concentrated, and the residue is dissolved in a solvent with high boiling point. Then, a basic compound is added to the obtained solution followed by stirring at 50 ° C to 100 ° C, in order to produce a compound of interest represented by the general formula (1a).

[0425] Alternatively, in the reaction of the compound of general formula (2) with the compound of general formula (3a), a basic compound is used in a molar ratio of the basic compound to the compound (2) which is between 0.9 : 1 and 2: 1. Stirring is carried out at 50 ° C to 100 ° C, so that the reaction of the compound of general formula (2) with the compound of general formula (3a) is carried out in a simple method to produce a compound of interest represented by the general formula (1a).

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322/854

Reaction scheme 2

R ^2a H (5) ---- ► basic compound o ₂ n

R ¹ CH ₂ R ^2a

OH basic compound O ₂ N ring closure

(1b) [0426] where R ¹ and Xi are as indicated above, and R ^2a represents a group represented by the general formula (A), (B), (E) or (F).

[0427] According to reaction scheme 2, the compound of the present invention represented by the general formula (1b) is produced by reacting a compound represented by the general formula (3b) with a compound represented by the general formula (5) or a compound thereof salt, in order to obtain a compound represented by the general formula (4b), and then subjecting the obtained compound to a ring closing reaction, in the presence of a basic compound.

[0428] The compound (3b) is unpublished, and a method for producing the compound will be explained later (reaction scheme 13). Compound (5), where R ^2a represents a group represented by the general formula (E), includes a novel compound. An example of methods of producing the above compound will be described later in Reference Examples 182, 186 to 188, and 192.

[0429] The molar ratio of the compound of general formula (3b) to the compound of general formula (5) can generally be between 1: 0.5 and 1: 5, and preferably between 1: 0.5 and 1:

2.

[0430] The reaction of the compound of general formula (3b) with the compound of general formula (5) is carried out in the presence of a basic compound in an appropriate solvent. [0431] As a basic compound and a reaction solvent, it is possible to use the same basic compound and the same reaction solvent as used in the reaction above the compound of general formula (2) with the compound of general formula (3a). The molar ratio of the basic compound to the compound of general formula (3b) is generally a catalytic amount, preferably between 0.1: 1 and 3: 1, and more preferably between

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323/854

0.1: 1 and 2: 1.

[0432] In the case of compound (5) where R ^2a represents a group represented by the general formula (B) or (E), the salt of compound (5) can be used instead of using compound (5) and a basic compound. Examples of a salt of the aforementioned type include alkali metal salts, such as a sodium salt or a potassium salt of the compound (5).

[0433] The reaction of the compound of general formula (3b) with the compound of general formula (5) is carried out, generally at room temperature up to 150 ° C, preferably at room temperature up to 120 ° C, and, more preferably, at room temperature up to 80 ° C. The reaction time is generally 10 minutes to 48 hours, preferably 10 minutes to 24 hours, and more preferably, 10 minutes to 2 hours.

[0434] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound of general formula (4b) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0435] The compound of the present invention represented by the general formula (1b) is produced by subjecting the compound represented by the general formula (4b) to a ring closing reaction. The ring closure reaction is carried out by dissolving the compound obtained above represented by the general formula (4b) in a reaction solvent and then adding a basic compound to this, followed by stirring at a certain temperature.

[0436] Here, as a reaction solvent and a basic compound, it is possible to use the same reaction solvent and the same basic compound as used in the reaction above the compound of general formula (3b) with the compound of general formula (5) .

[0437] The molar ratio of the basic compound to the compound of the general formula (4b) is generally equal to 1: 1 or greater, preferably between 1: 1 and 5: 1, and more preferably between 1: 1 and 2 : 1.

[0438] The reaction temperature for the ring closing reaction is

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324/854 generally from 0 ° C to 150 ° C, preferably from room temperature to 120 ° C, and more preferably from 50 ° C to 100 ° C. The reaction time is generally 10 minutes to 48 hours, preferably 10 minutes to 24 hours, and more preferably, 20 minutes to 4 hours.

[0439] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound of general formula (1 b) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0440] In the present invention, the reaction mixture can be subjected directly to the following ring closure reaction without isolating the compound of general formula (4b) produced as a result of the reaction of the compound of general formula (3b) with the compound of general formula (5), in order to produce a compound of interest which is the compound of the present invention represented by the general formula (1b).

[0441] Particularly, in the case of compound (5) where R ^2a represents a group represented by the general formula (B) or (E), if a basic compound for compound (5) is used at a molar ratio equal to 1 : 1 or greater, and if the reaction is carried out at 50 ° C to 100 ° C, the compound of the present invention represented by the general formula (1b) can be produced in a simple method without isolating an intermediate (4). In the case of using the alkali metal salt (for example, a sodium salt or a potassium salt) of compound (5) where R ^2a represents a group represented by the general formula (B) or (E), affirm the same.

Reaction scheme 3

[0442] where R ⁴¹ and Xi are as indicated above.

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325/854 [0443] According to reaction scheme 3, the compound of the present invention represented by the general formula (1c) is produced by reacting the compound represented by the general formula (2) with a compound represented by the general formula (3c) in order to obtain a compound represented by the general formula (4c), and then subjecting the obtained compound to a ring closing reaction, in the presence of a basic compound.

[0444] The compound (3c) includes a novel compound, and a method for producing the compound will be explained later (reaction scheme 14).

[0445] The molar ratio of the compound of general formula (2) to the compound of general formula (3c) can generally be between 0.1: 1 and 2: 1, preferably between 0.1: 1 and 1: 1, and , more preferably, between 0.1: 1 and 0.5: 1.

[0446] The reaction of the compound of general formula (2) with the compound of general formula (3c) is carried out in the presence of a basic compound in an appropriate solvent. [0447] As a basic compound and a reaction solvent, it is possible to use the same basic compound and the same reaction solvent as used in the reaction above the compound of general formula (2) with the compound of general formula (3a). The molar ratio of the basic compound to the compound of general formula (2) is generally 0.1: 1 or greater, preferably between 1: 1 and 5: 1, and more preferably between 1: 1 and 2: 1 .

[0448] The reaction of the compound of general formula (2) with the compound of general formula (3c) is carried out, for example, as follows: The compound of general formula (2) is dissolved in a reaction solvent, and, while stirring, a basic compound is added to the mixture cooled on ice or to room temperature (30 ° C). Then, the mixture is stirred at room temperature to 80 ° C for 30 minutes to 1 hour, and the compound of general formula (3c) is then added to this. Then, the mixture is further stirred, usually at room temperature to 100 ° C, and preferably from 50 ° C to 80 ° C, usually for 30 minutes to 24 hours, preferably for 1 to 12 hours, and, more preferably, for 1 to 8 hours.

[0449] The reaction mixture thus obtained is cooled, for example, and then its

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326/854 crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound of general formula (4c) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization. [0450] The compound of the present invention represented by the general formula (1c) is produced by subjecting the compound represented by the general formula (4c) to a ring closing reaction. The ring closing reaction is carried out by dissolving the compound obtained above represented by the general formula (4c) in a reaction solvent and then adding a basic compound to this followed by stirring at a certain temperature.

[0451] Here, as a reaction solvent and a basic compound, it is possible to use the same reaction solvent and the same basic compound as used in the reaction above the compound of general formula (2) with the compound of general formula (3c) . [0452] The molar ratio of the basic compound to the compound of the general formula (4c) is generally equal to 1: 1 or greater, preferably between 1: 1 and 5: 1, and more preferably between 1: 1 and 2 : 1.

[0453] The reaction temperature for the ring closure reaction is generally from 0 ° C to 150 ° C, preferably from room temperature to 120 ° C, and more preferably from 50 ° C to 100 ° C. The reaction time is generally 30 minutes to 48 hours, preferably 1 to 24 hours, and more preferably, 1 to 12 hours.

[0454] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound of general formula (1c) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization. [0455] In the present invention, the reaction mixture can be subjected directly to the following ring closure reaction without isolating the compound of general formula (4c) generated as a result of the reaction of the compound of general formula (2) with the compound of general formula (3c), so that it is possible to produce the compound of

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327/854 interest of the present invention represented by the general formula (1c).

Reaction scheme 4

(1-A-A9) [0456] where R ^{1 and} n are as indicated above, R ^3a represents a C 1-6 alkoxy group - C 1-6 alkyl and R ^3b represents a C 1-6 alkanoyl group.

[0457] A compound in which, in the general formula (1), R ² represents a group represented by the general formula (A) and R ³ represents A1) a hydrogen atom (hereinafter referred to as a compound (1-A-A1 )), is produced by hydrolysis of a corresponding compound in which R ³ represents A3) a C1-6 alkoxy group (C1-6 alkyl) (hereinafter referred to as a compound (1-A-A3)), or a compound corresponding wherein R ³ represents A9) a C 1-6 alkanoyl group (referred to below as a compound (1-A-A9)).

[0458] Hydrolysis of the compound (1-A-A3) is carried out under acidic conditions. Hydrolysis is carried out, for example, by suspending or dissolving the compound (1-A-A3) in an appropriate solvent, and adding acid to the solution obtained, followed by stirring at 0 ° C to 120 ° C. Examples of the solvent used can include water, alcohol solvents, such as methanol, ethanol, isopropanol or ethylene glycol, acetonitrile, acetone, toluene, DMF, DMSO, acetic acid, trifluoroacetic acid, and mixed solvents thereof. Examples of the acid used can include organic acids,

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328/854 such as trifluoroacetic acid or acetic acid, and inorganic acids, such as hydrochloric acid, boric acid, hydrobromic acid or sulfuric acid. Organic acids, such as trifluoroacetic acid or acetic acid can also be used as reaction solvents. The reaction temperature is generally from 0 ° C to 120 ° C, preferably from room temperature to 100 ° C, and, more preferably, from room temperature to 80 ° C. The reaction time is generally from 30 minutes to 24 hours, preferably from 30 minutes to 12 hours, and more preferably from 1 to 8 hours.

[0459] Hydrolysis of the compound (1-A-A9) is carried out under basic conditions. Hydrolysis is carried out, for example, by suspending or dissolving the compound (1-A-A9) in an appropriate solvent, and adding base to the solution obtained, followed by stirring at 0 ° C to 120 ° C. Examples of the solvent used can include water, alcohol solvents, such as methanol, ethanol, isopropanol or ethylene glycol, and mixed solvents thereof. Examples of the base used can include alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkali metal carbonate, such as sodium carbonate or potassium carbonate, and acetates, such as sodium acetate. The reaction temperature is generally from 0 ° C to 120 ° C, preferably from room temperature to 100 ° C, and, more preferably, from room temperature to 80 ° C. The reaction time is generally from 30 minutes to 24 hours, preferably from 30 minutes to 12 hours, and more preferably from 1 to 8 hours.

[0460] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound (1-AA1) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

Reaction scheme 5

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329/854

O ₂ N

R ^3aa SO ₂ X ₂ (1-A-A1)

(1-A-A7) [0461] where R ^{1 and} n are as indicated above, X2 represents a halogen atom, and R ^3aa represents a C1-6 alkyl group or phenyl group that can be replaced by the C1-6 alkyl group .

[0462] A compound in which, in the general formula (1), R ² represents a group represented by the general formula (A) and R ³ represents a sulfonyl group of definitions A7) or A8) (hereinafter referred to as a compound (1 -A-A7)), is produced by sulfonylation of a corresponding compound in which R ³ represents A1) a hydrogen atom (the compound (1-A-A1)).

[0463] For the suphonylation of the compound (1-A-A1), it is possible to apply widely reaction conditions for the common alcohol sulfonylation reaction. For example, compound (1-A-A1) is dissolved in an appropriate solvent, and the compound represented by the general formula R ^3aa SO2X2 is added to the solution obtained in the presence of a basic compound followed by stirring at 0 ° C to 150 ° C ° C, so that it is possible to obtain the compound (1-A-A7).

[0464] Any solvent can be used here, as long as it does not inhibit the sulfonylation reaction. Examples of a solvent of the aforementioned type include hydrogenated hydrocarbon solvents, such as methylene chloride or chloroform, polar aprotic solvents such as DMF, DMSO or acetonitrile, aromatic hydrocarbon solvents such as benzene, toluene or xylene, hydrocarbon solvents, such as tetralin, liquid paraffin or cyclohexane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl or diglyme ether, ethyl acetate, acetone, and mixed solvents thereof.

[0465] The compound represented by the general formula R ^3aa SO2X2 is used with the compound (1-A-A1) in a molar ratio generally equal to 1: 1 or greater, preferably between 1: 1 and 2: 1, and more preferably, between 1: 1 and 1.1: 1.

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330/854 [0466] As a basic compound, it is possible to use the same basic compound as used in the reaction above the compound of general formula (2) with the compound of general formula (3a).

[0467] The molar ratio of the basic compound to the compound represented by the general formula R ^3aa SO2X2 is generally equal to 1: 1 or greater, preferably between 1: 1 and 5: 1, and more preferably between 1: 1 and 2: 1.

[0468] In the present sulfonylation reaction, it is possible to use 4dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine or the like as a catalyst.

[0469] The reaction temperature is generally 0 ° C to 150 ° C, preferably 0 ° C to 100 ° C, and more preferably, 0 ° C to 60 ° C. The reaction time is generally 30 minutes to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 4 hours.

[0470] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound (1-AA7) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

Reaction scheme 6

O ₂ N

(1-A-A7)

(1b) [0471] where R ¹ , R ^2a , R ^{3aa and} n are as indicated above.

[0472] A compound in which, in the general formula (1), R ² represents a group represented by the general formula (A), (B), (E) or (F) (hereinafter referred to as a compound (1b)) , is also produced by a reaction of a corresponding compound in which R ² represents a group represented by the general formula (A) and R ³ represents a sulfonyl group of definitions A7) or A8) (a compound (1-A-A7 ))

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331/854 with a compound represented by the general formula (5).

[0473] The reaction of the compound (1-A-A7) with the compound represented by the general formula (5) is carried out in an appropriate solvent in the presence of a basic compound. [0474] Any solvent can be used here, as long as it does not inhibit the present reaction. Examples of a solvent of the aforementioned type include water, polar aprotic solvents such as DMF, DMSO or acetonitrile, hydrocarbon solvents such as benzene, toluene, xylene, tetraline, liquid paraffin or cyclohexane, alcohol solvents such as ethanol, isopropanol, n-butanol or ter-butanol, ether solvents, such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, ethyl acetate, acetone, and mixed solvents thereof.

[0475] As a basic compound, it is possible to use the same basic compound as used in the reaction above the compound of general formula (2) with the compound of general formula (3a).

[0476] The molar ratio of the basic compound to the compound (1-A-A7) is generally equal to 1: 1 or greater, preferably between 1: 1 and 5: 1, and more preferably between 1: 1 and 2: 1.

[0477] The molar ratio of the compound represented by the general formula (5) to the compound (1-A-A7) can generally be equal to 1: 1 or greater, preferably between 0.9: 1 and 2: 1, and , more preferably, between 0.9: 1 and 1.5: 1.

[0478] The reaction temperature is generally from room temperature to 150 ° C, preferably from room temperature to 100 ° C, and, more preferably, from 60 ° C to 100 ° C. The reaction time is generally 10 minutes to 24 hours, preferably 10 minutes to 12 hours, and more preferably, 20 minutes to 7 hours.

[0479] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, a compound of interest can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization. Reaction scheme 7

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332/854

(1-A-A1)

O ₂ N carbamation

(1-D) [0480] where R ¹ , n, R ⁷ and R ⁸ are as indicated above.

[0481] A compound in which, in the general formula (1), R ² represents a group represented by the general formula (D) (hereinafter referred to as a compound (1-D)), is produced by the carbamation of a compound where R ² represents a group represented by the general formula (A) and R ³ represents A1) a hydrogen atom (the compound (1-A-A1)).

[0482] For the carbamation of the compound (1-A-A1), it is possible to apply widely reaction conditions for the common alcohol carbamation reaction. Examples of a method of the aforementioned type include: (1) a method that uses amine represented by a general formula R ⁷ R ⁸ NH (where R ⁷ and R ⁸ are as indicated above) and triphosgene, (2) a utilization reaction of amine represented by a general formula R ⁷ R ⁸ NH (where R ⁷ and R ⁸ are as indicated above) and carbodiimidazole, and (3) a method using an isocyanate compound.

[0483] (1) Method using amine and triphosgene [0484] Amine represented by the general formula R ⁷ R ⁸ NH (where R ⁷ and R ⁸ are as indicated above) is reacted with triphosgene, in order to generate carbamoyl chloride represented by a general formula C1CONR ⁷ R ⁸ (where R ⁷ and R ⁸ are as indicated above). Carbamoyl chloride can be isolated. However, as it is generally unstable, it is used immediately in the next step without isolation.

[0485] A basic compound and amine above are added to a solution of methylene chloride containing triphosgene, while the solution is cooled and stirred. Then, the mixture is stirred at 0 ° C to 30 ° C for 30 minutes to 4 hours, in order to generate carbamoyl chloride. The molar ratio of triphosgene to amine is generally between 0.3: 1 and 1.5: 1, preferably between 0.3: 1 and 0.6: 1, and more preferably between 0.3: 1 and 0 , 4: 1.

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333/854 [0486] Examples of a basic compound used in the reaction between amine and triphosgene include triethylamine, N-ethyldiisopropylamine, and N-methylmorpholine. The molar ratio of a basic compound to triphosgene is generally 3: 1 or greater, preferably between 3: 1 and 4.5: 1, and more preferably between 3: 1 and 3.3: 1.

[0487] The reaction temperature is generally 0 ° C to 60 ° C, and preferably 0 ° C to room temperature (30 ° C). The reaction time is generally 30 minutes to 8 hours, preferably 1 to 4 hours, and more preferably, 1 to 2 hours.

[0488] The reaction solution thus obtained from carbamoyl chloride can be used directly. However, it is more advantageous to eliminate insoluble products by filtration before the filtrate concentration.

[0489] Subsequently, the compound (1-A-A1) is dissolved in an appropriate reaction solvent, and the carbamoyl chloride produced above is added to this, while stirring with ice cooling. Then, more copper chloride is added to this, and the mixture is stirred at a certain temperature for a certain time, in order to produce the compound (1-D).

[0490] Any reaction solvent can be used widely here, as long as it does not inhibit the reaction. Examples of a solvent of the type referred to may include polar aprotic solvents, such as DMF, DMSO or acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl or diglyme ether, acetone, ethyl acetate, and mixed solvents thereof.

[0491] The molar ratio of carbamoyl chloride to compound (1-A-A1) can generally be between 1: 1 and 5: 1, preferably between 1: 1 and 3: 1, and more preferably between 1: 1 and 2: 1.

[0492] Furthermore, the molar ratio of copper chloride to the compound (1-A-A1) can generally be between 0.1: 1 and 5: 1, preferably between 0.5: 1 and 2: 1, and, more preferably, between 0.5: 1 and 1: 1.

[0493] The reaction temperature is generally 0 ° C to 60 ° C, preferably from

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334/854

10 ° C to 50 ° C, and more preferably, 20 ° C to 35 ° C. The reaction time is generally 30 minutes to 48 hours, preferably 1 to 30 hours, and more preferably, 2 to 24 hours.

[0494] (2) Reaction using amine and carbodiimidazole [0495] Amine represented by the general formula R ⁷ R ⁸ NH (where R ⁷ and R ⁸ are as indicated above) is dissolved in an appropriate reaction solvent. 1,1'carbonyldiimidazole is added to the obtained solution, while stirring with ice. The obtained mixture is stirred at a certain temperature for a certain time, in order to obtain an amino carbonylimidazole derivative.

[0496] The molar ratio of 1,1'-carbonyldiimidazole to amine is generally between 0.9: 1 and 2: 1, preferably between 1: 1 and 1.5: 1, and more preferably between 1: 1 and 1.2: 1.

[0497] Examples of the solvent used may include polar aprotic solvents, such as acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, acetone, ethyl acetate, and mixed solvents thereof.

[0498] The reaction temperature is generally 0 ° C to 60 ° C, and preferably 0 ° C to room temperature (30 ° C). The reaction time is generally 30 minutes to 8 hours, preferably 1 to 4 hours, and more preferably, 1 to 2 hours.

[0499] The compound (1-A-A1) is dissolved in an appropriate solvent in advance. Then, the amino carbonylimidazole derivative thus obtained is added to the solution, while stirring with ice. Then, more copper chloride is added, and the mixture is stirred at a certain temperature for a certain time, in order to produce the compound (1-D).

[0500] Any solvent can be used here as a reaction solvent, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type may include polar aprotic solvents, such as DMF, DMSO or acetonitrile, solvents of

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335/854 hydrocarbon, such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, acetone, ethyl acetate, and mixed solvents thereof.

[0501] The molar ratio of the amino carbonylimidazole derivative to the compound (1 A-A1) can generally be between 1: 1 and 5: 1, preferably between 1: 1 and 3: 1, and more preferably between 1 : 1 and 2: 1.

[0502] Furthermore, the molar ratio of copper chloride to the compound (1-A-A1) can generally be between 0.9: 1 and 5: 1, preferably between 1: 1 and 2: 1, and, more preferably, between 1: 1 and 1.2: 1.

[0503] The reaction temperature is generally 0 ° C to 60 ° C, preferably 10 ° C to 50 ° C, and more preferably 20 ° C to 35 ° C. The reaction time is generally 30 minutes to 48 hours, preferably 1 to 30 hours, and more preferably 1 to 3 hours.

[0504] (3) Method using isocyanate [0505] The compound (1-A-A1) is dissolved in an appropriate reaction solvent. Then, isocyanate is added to the solution, while stirring with ice. Then, more copper chloride is added, and the mixture is stirred at a certain temperature for a certain time, to produce a compound (1-D) in which R ⁷ or R ⁸ represents a hydrogen atom. .

[0506] Any solvent can be used here as a reaction solvent, as long as it does not inhibit the reaction. Examples of a solvent of the type referred to may include polar aprotic solvents, such as DMF, DMSO or acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl or diglyme ether, acetone, ethyl acetate, and mixed solvents thereof.

[0507] The molar ratio of the isocyanates to the compound (1-A-A1) can generally be between 1: 1 and 5: 1, preferably between 1: 1 and 3: 1, and more preferably between 1: 1 and 2: 1.

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336/854 [0508] In addition, the molar ratio of copper chloride to the compound (1-A-A1) can generally be between 0.9: 1 and 5: 1, preferably between 1: 1 and 2: 1 , and, more preferably, between 1: 1 and 1.2: 1.

[0509] The reaction temperature is generally 0 ° C to 60 ° C, preferably 10 ° C to 50 ° C, and more preferably 20 ° C to 35 ° C. The reaction time is generally 30 minutes to 48 hours, preferably 1 to 30 hours, and more preferably 1 to 3 hours.

[0510] The reaction mixture obtained using the above method (1), (2) or (3) is cooled, for example, and then its crude reaction product is separated from it by means of an insulation operation. , such as filtration, concentration or extraction. Then, the compound (1-D) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0511] A compound having a heterocycle containing a nitrogen atom in a molecule thereof and comprising a C1-6 alkoxycarbonyl group substituted on the nitrogen atom of the heterocycle selected above from the compounds of the present invention represented by the general formula (1) can be converted by deprotection to a compound having a hydrogen atom which is replaced by the nitrogen atom of the corresponding heterocycle.

[0512] According to this method, for example, a starting material to be unprotected is dissolved in an appropriate reaction solvent, followed by hydrolysis using acid, in order to obtain a compound of interest.

[0513] Any solvent can be used here as a reaction solvent, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type may include water, alcohol solvents such as methanol or ethanol, polar aprotic solvents such as DMSO or acetonitrile, hydrocarbon solvents such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl or diglyme ether, acetone, ethyl acetate, and mixed solvents thereof.

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337/854 [0514] Examples of acid include inorganic acids, such as hydrochloric acid, boric acid or hydrobromic acid, and organic acids, such as acetic acid, trifluoroacetic acid or trichloroacetic acid. Of these, the use of trifluoroacetic acid is advantageous.

[0515] The molar ratio of said acid to the starting material is generally equal to 1: 1 or greater, and preferably between 2: 1 and 10: 1. However, said acid can also be used in an amount in large excess as a reaction solvent. The reaction temperature is generally from room temperature to 100 ° C, but can be adjusted more appropriately depending on the type of acid used. When using trifluoroacetic acid, just adjust to room temperature. The reaction time is generally 1 to 24 hours, and preferably 1 to 12 hours.

[0516] The reaction mixture thus obtained is concentrated, and, if necessary, acid, such as hydrochloric acid, is added for crystallization, so that it is possible to isolate a compound of interest in a form of hydrochloride or trifluoroacetate by means of recrystallization or the like.

[0517] The compound of unprotected interest can be isolated as described above. Alternatively, a basic compound, such as triethylamine, is added to this without isolation, so that the compound of interest is converted to a free compound, which can be used in the next reaction.

[0518] For example, the free base compound of interest indicated above is reacted with an acid halide, acid anhydride or mixed acid anhydride, so that it is possible to produce the corresponding carbamate or amide. The reaction of the free base compound of interest indicated above with sulfonyl chloride allows the production of the corresponding sulfonamide. Furthermore, the urea reaction of the free base compound indicated above with amine allows the production of the corresponding urea. In addition, the reductive amination of the free base compound of interest indicated above with aldehyde or the alkylation of the same compound above with alkyl halide allows the production of the N-alkylated derivative of the compound of interest indicated above.

[0519] A compound showing a heterocycle containing an atom of

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338/854 nitrogen in a molecule thereof and comprising a hydrogen atom substituted in the nitrogen atom of the heterocycle selected above from the compounds of the present invention represented by the general formula (1) can be converted by means of carbamation to a compound presenting -COOR ²⁷ (where R ²⁷ is the same as above) substituted on the nitrogen atom of the corresponding heterocycle.

[0520] Examples of a carbamation method include (1) a method using various types of halogenated forms and (2) a method using an active intermediate obtained by reacting alcohol with carbonyldiimidazole.

[0521] (1) Method using halogenated formate [0522] A starting material is reacted with halogenated formate in a reaction solvent in the presence of a basic compound, in order to produce a compound of interest.

[0523] Any solvent can be used here as a reaction solvent, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type may include polar aprotic solvents, such as DMSO or acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, solvents of ether, such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, acetone, ethyl acetate, and mixed solvents thereof.

[0524] Known compounds can be used widely as a basic compound here. Examples of a basic compound of the aforementioned type include basic inorganic compounds, such as hydroxide, carbonate or hydrogen carbonate, and basic organic compounds, such as acetate.

[0525] Specific examples of hydroxide include sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide. Specific examples of carbonate include sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate. Specific examples of hydrogen carbonate include sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate and lithium hydrogen carbonate.

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339/854 [0526] Specific examples of acetate include sodium acetate and potassium acetate. In addition to these compounds, specific examples of other basic organic compounds include triethylamine, trimethylamine, diisopropylethylamine, pyridine, dimethylaniline, 1-methylpyrrolidine, N-methylmorpholine, DBN, DBU, and DABCO.

[0527] The molar ratio of a basic compound of the type referred to for the starting material can generally be between 1: 1 and 4: 1, preferably between 1: 1 and 1.5: 1, and more preferably between 1 : 1 and 1.1: 1.

[0528] The molar ratio of halogenated formate of the type referred to the starting material can generally be equal to 1: 1 or greater, preferably between 1: 1 and 1.5: 1, and more preferably between 1: 1 and 1.1: 1.

[0529] The reaction temperature is generally 0 ° C to 100 ° C, preferably 0 ° C to 60 ° C, and more preferably, 10 ° C to 30 ° C. The reaction time is generally from 30 minutes to 12 hours, preferably from 1 to 6 hours, and more preferably from 1 to 2 hours.

[0530] (2) Method using active intermediate [0531] Alcohol represented by a general formula R ²⁷ OH (R ²⁷ is the same as above) is reacted with 1, Τ-carbonyldiimidazole in a suitable solvent to obtain an active intermediate ( the first step), and then the active intermediate obtained is reacted with a starting material (the second step), so that it is possible to produce a compound of interest.

[0532] Any solvent can be used here as a reaction solvent, as long as it does not inhibit the reaction. Examples of a solvent of the type referred to may include polar aprotic solvents, such as DMF, DMSO or acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl or diglyme ether, acetone, ethyl acetate, and mixed solvents thereof.

[0533] The molar ratio of 1, Τ-carbonyldiimidazole to alcohol represented by the general formula above can generally be equal to 1: 1 or greater, preferably between 1: 1 and 1.5: 1, and more preferably between 1: 1 and 1.1: 1.

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340/854 [0534] In the first step, the reaction temperature is generally 0 ° C to 100 ° C, preferably 0 ° C to 60 ° C, and more preferably 10 ° C to 30 ° C. The reaction time is generally from 30 minutes to 12 hours, preferably from 1 to 6 hours, and more preferably from 1 to 2 hours.

[0535] The molar ratio of the active intermediate to the starting material can generally be 1: 1 or greater, preferably between 1: 1 and 1.5: 1, and more preferably between 1: 1 and 1, 1: 1.

[0536] In a second step, the reaction temperature is generally 0 ° C to 100 ° C, preferably 0 ° C to 60 ° C, and more preferably, 10 ° C to 30 ° C. The reaction time is generally from 30 minutes to 12 hours, preferably from 1 to 6 hours, and more preferably from 1 to 2 hours.

[0537] The reaction mixture obtained using method (1) or (2) above is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the carbamate of interest can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0538] A compound having a heterocycle containing a nitrogen atom in a molecule thereof and comprising a group R ³² R ³³ NCO (where R ³² and R ³³ are as indicated above) substituted on the nitrogen atom of the heterocycle selected above from the compounds of the present invention represented by the general formula (1) can be produced by reacting a compound having a hydrogen atom substituted on the nitrogen atom of the corresponding heterocycle.

[0539] For urea formation of the type referred to, for example, (1) a method using amine represented by a general formula R ³² R ³³ NH (where R ³² and R ³³ are as indicated above) and triphosgene, (2 ) an amine utilization reaction represented by the general formula R ³² R ³³ NH (where R ³² and R ³³ are as indicated above) and carbodiimidazole, and (3) a method using an isocyanate compound.

[0540] These reactions (1), (2) and (3) are carried out, for example, in the same

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341/854 reaction conditions for reactions with compound (1-A-A1) as described in (1), (2) and (3) above.

[0541] The reaction mixture obtained by method (1), (2) or (3) above is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, as filtration, concentration or extraction. Then, a compound of interest can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0542] As for the compounds of the present invention represented by the general formula (1), a compound having a heterocycle containing a nitrogen atom in a molecule thereof and comprising a R ^38a group substituted on the nitrogen atom of the above heterocycle (where R ^38a represents a C1-6 alkanoyl group, C2-C6 phenyl alkanoyl group (where, in the phenyl ring, at least one type of group selected from a group consisting of halogen atom, an unsubstituted or substituted C1-6 alkyl group halogen and an unsubstituted or substituted halogen C1-6 alkoxy group can be substituted), phenoxy C2-C6 alkanoyl group in which halogen atom can be substituted in the phenyl ring, phenylthio alkanoyl C2-C6 group in which halogen can be substituted in the phenyl ring, benzoyl group (where, in the phenyl ring, at least one type of group selected from a group consisting of halogen, an unsubstituted or substituted C1-6 alkyl group halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a C1-6 alkylamino group can be substituted), 4-biphenylcarbonyl group, pyridinylcarbonyl group, phenyl C2-C6 alkenylcarbonyl group or group in which halogen atom can be substituted on the phenyl ring), it can be produced by reacting a compound comprising a hydrogen atom substituted on the nitrogen atom of the corresponding heterocycle, with carboxylic acid represented by a general formula R ^38a OH (where R ^38a OH is the same than above).

[0543] The above reaction can be carried out under the same conditions for a reaction of a compound (Ea-2) with a compound (18) represented by

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342/854 reaction scheme 19, which will be described later.

[0544] The reaction mixture obtained using the above method is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, a compound of interest can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0545] A compound having a heterocycle containing a nitrogen atom in a molecule thereof and comprising R ^39a SO2 substituted on the nitrogen atom of the above heterocycle (where R ^39a represents a phenyl group that can be substituted by at least one selected group of a group consisting of a halogen atom and C 1 -alkyl groups), selected from the compounds of the present invention represented by the general formula (1), can be produced by reacting a compound having a hydrogen atom substituted on the nitrogen atom of the corresponding heterocycle, with sulfonyl halide represented by a general formula R ^39a SO2X2 (where R ^39a and X2 are as indicated above).

[0546] The above reaction can be carried out under the same conditions for a reaction of the compound (Fd-1) with a compound (15) represented by reaction scheme 18, which will be described further below.

[0547] The reaction mixture obtained by the above method is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, a compound of interest can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0548] As for the compounds of the present invention represented by the general formula (1), a compound having a heterocycle containing a nitrogen atom in a molecule thereof and comprising a group R ^40a -CH-R ⁵² substituted on the nitrogen atom of the heterocycle above (where R ⁵² is the same

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343/854 as described later, and R ^40a represents a phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of halogen atom, a cyano group, an unsubstituted C1-6 alkyl group or substituted by halogen, a cyclohexyl group, an amino group that may have a C1-6 alkyl group as a substituent, a C1-6 alkoxycarbonyl group, a phenoxy group, a phenyl C1-6 alkyl group, a phenyl alkenyl group C2-C6, a pyridyl group, an imidazolyl group, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a piperidinyl group can be substituted), 4-biphenylyl group (where, in the phenyl ring, at least one group selected from a group consisting of a halogen atom, a cyano group, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and an amino group that may have a group C1-6 alkyl as a substitin te can be substituted), naphthyl group, furyl group, or thienyl group), can be produced by subjecting a compound comprising a hydrogen atom substituted on the nitrogen atom of the heterocycle corresponding to a reductive alkylation reaction.

[0549] This reductive alkylation reaction is carried out, for example, by reacting a starting material with aldehyde or ketone represented by a general formula

R ₄ q ^ _{c =} o

R ⁵² [0550] (R ^40a is the same as described above, and R ⁵² is a hydrogen atom or C 1 -C alkyl group) in an appropriate solvent in the presence of the reducing agent. [0551] This reaction can be carried out in the same condition [as] for a reaction of a compound (E-2) with a compound (13) represented by reaction scheme 16, which will be described later.

[0552] The reaction mixture obtained using the method described above is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, a compound of interest can be isolated and purified from the reaction mixture through a common purification operation, such as

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344/854 column chromatography or recrystallization.

Reaction scheme 8

O ₂ N

deprotection

(1-F-Fc16c)

O ₂ N

(1-F-Fc16d)

R ⁴² —NCO

O ₂ N

v

[0553] where R ¹ , X2 and n are as indicated above, R ^24a represents a group represented by each of (Fca1) to (Fca11), R ^42a represents a C1 alkyl group

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345/854

6, R ⁴² represents a group represented by (Fca5), (Fca6) or (Fca7), R ^42c represents a group represented by (Fca2), (Fca3), (Fca4), (Fca8) or (Fca9), and R ^42b represents a phenyl group (where at least one selected from unsubstituted or halogen-substituted C1-6 alkyl groups can be substituted on the phenyl ring).

[0554] The reaction of converting a compound (1-F-Fc16a) to a compound (1-FFc16b) can be carried out under the same conditions as the reaction of converting a compound (E-1) to a compound (E-2) represented by reaction scheme 16, which is described below.

[0555] The reaction mixture thus obtained is concentrated, and if necessary, acid, such as hydrochloric acid, is added for crystallization, so that it is possible to isolate a compound of interest in a form of hydrochloride or trifluoroacetate by means of recrystallization or the like.

[0556] A compound (1-F-Fc16c) is produced by reacting the compound (1-FFc16b) with R ^42c X2. This reaction can be carried out under the same condition as for a reaction of the compound (Fd-1) with the compound (15) represented by the reaction scheme 18, which is described below.

[0557] A compound (1-F-Fc16d) is produced by reacting the compound (1-FFc16b) with R ⁴² OH. This reaction can be carried out under the same condition as for a reaction of the compound (Ea-2) with the compound (18) represented by the reaction scheme 19, which is described below.

[0558] The reaction mixture obtained using the above method is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, a compound of interest can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0559] A compound (1-F-Fc16e) is produced by reacting the compound (1-FFc16b) with R ^42b -NCO. This reaction can be carried out in the presence or absence of, preferably in the absence of, a basic compound, in an appropriate inert solvent or without a solvent. Here, as a solvent and a basic compound, one can

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346/854 use the solvent and basic compound as follows. Examples of a basic compound of the aforementioned type include: organic bases, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1 , 8-diazabicyclo [5.4.0] undecene-7 (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO); inorganic bases including carbonates, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, metal hydroxides, such as sodium hydroxide, potassium hydroxide or calcium hydroxide, potassium hydride, sodium hydride, potassium, sodium , sodium amide, and metal alcoholates, such as sodium methylate or sodium ethylate. In addition, examples of a solvent include halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane or carbon tetrachloride, aromatic hydrocarbons, such as benzene, toluene or xylene, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dimethoxy ethane, esters, as acetates methyl, ethyl acetate or isopropyl acetate, alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl celosolve or methyl celosolve, acetonitrile, pyridine, acetone, water, polar solvents aprotic, such as N, N-dimethylacetamide, Ν, Ν-dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide, and mixed solvents thereof. The molar ratio of compound R ^42b -NCO to compound (1-F-Fc16b) can generally be between 1: 1 and 5: 1, and preferably equal to 1: 1 and 3: 1. The reaction is carried out generally from 0 ° C to 200 ° C, and preferably from room temperature to 150 ° C, generally for 5 minutes to 30 hours. In the reaction, it is possible to add a boron compound, such as boron trifluoride complex - diethyl ether, or a halogenated copper compound, such as cuprous chloride.

[0560] The reaction mixture thus obtained is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, a compound of interest can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization. Reaction scheme 9

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347/854

0 ₂ N

(1-Fda)

N — N — COOR ^42a

the ₂ n

N — NH ₂ (1-Fdb) where R ^42a , R ^{1 and} n are as indicated above.

A compound (1-Fdb) is produced by deprotecting a [0561] [0562] compound (1-Fda). For example, the compound (1-Fda) is dissolved in an appropriate reaction solvent followed by hydrolysis with acid, in order to obtain the compound (1 Fdb).

[0563] Any reaction solvent can be used widely here, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type include water, alcohol solvents such as methanol or ethanol, polar aprotic solvents such as DMSO or acetonitrile, hydrocarbon solvents such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, acetone, ethyl acetate, and mixed solvents thereof. [0564] Examples of acid include inorganic acids, such as hydrochloric acid, hydrobromic acid or boric acid, and organic acids, such as acetic acid, trifluoroacetic acid or trichloroacetic acid. Of these, trifluoroacetic acid is used to advantage.

[0565] The molar ratio of said acid to the compound (1-Fda) is generally equal to 1: 1 or greater, and preferably between 2: 1 and 10: 1. However, said acid

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348/854 can also be used in a large excess as a reaction solvent. The reaction temperature is generally from room temperature to 100 ° C, it can be adjusted accordingly depending on the type of acid used. When using trifluoroacetic acid, it is sufficient to adjust to room temperature. The reaction time is generally 1 to 24 hours, and preferably 1 to 12 hours.

[0566] The reaction mixture thus obtained is concentrated, and, if necessary, acid, such as hydrochloric acid, is added for crystallization, so that the compound (1-Fdb) can be isolated in a form of hydrochloride or trifluoroacetate by recrystallization or similar.

Reaction scheme 10

[0567] where R ^42a , R ¹ , n, R ³⁴ and R ³⁵ are as indicated above.

[0568] A compound (1-Fdc) is produced by reacting the compound (1-Fda) with aldehyde or ketone represented by a general formula R ³⁴ COR ³⁵ (where R ³⁴ and R ³⁵ are as indicated above).

[0569] This reaction is carried out in the presence of acid in an appropriate solvent. [0570] Any reaction solvent can be used widely here, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type include water, alcohol solvents, such as methanol or ethanol, polar aprotic solvents, such as DMSO or acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline or

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349/854 liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, acetone, ethyl acetate, and mixed solvents thereof . [0571] Examples of acid include inorganic acids, such as hydrochloric acid, hydrobromic acid or boric acid, and organic acids, such as acetic acid, trifluoroacetic acid or trichloroacetic acid. Of these, trifluoroacetic acid is used to advantage.

[0572] The molar ratio of said acid to the compound (1 -Fda) is generally 0.5: 1 or greater, and preferably between 0.5: 1 and 1.5: 1. However, referred to acid can also be used in a large excess as a reaction solvent.

[0573] The molar ratio of aldehyde or ketone to the compound (1-Fda) is generally between 0.9: 1 and 3: 1, preferably between 1: 1 and 1.5: 1, and more preferably between 1: 1 and 1.3: 1.

[0574] The reaction temperature is usually from room temperature to 100 ° C, but can be adjusted accordingly depending on the type of acid used. The reaction time is generally 1 to 12 hours, and preferably 1 to 3 hours.

[0575] The reaction mixture thus obtained is concentrated, and if necessary, acid, such as hydrochloric acid, is added for crystallization, so that the compound (1-Fdc) can be isolated in a form of hydrochloride or trifluoroacetate by recrystallization or similar.

[0576] Next, a method for producing a starting material and an intermediate used for producing the compound of the present invention is explained.

Reaction scheme 11

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350/854

[0577] where R ¹ , R ⁷ , R ⁸ , Xi and n are as indicated above, and R ^3c represents a C1-6 alkoxy group - C1-6 alkyl, a C1-6 alkanoyl group or a p-nitrobenzoyl group.

[0578] The reaction to lead from a compound (4d) to a compound (4e) is carried out, for example, under the same reaction conditions as for the reaction that leads to the compound (1-A-A3) or compound (1- A-A9) to compound (1-A-A1) as shown in reaction scheme 4. For example, in the case of compound (4d) where R ^3c represents a C1-6 alkoxy group - C1-6 alkyl it may be appropriate to carry out the reaction under the same conditions as for the reaction that leads from the compound (1-A-A3) to the compound (1-A-A1). In the case of compound (4d) where R ^3c represents a C1-6 alkanoyl group or pnitrobenzyl, it may be appropriate to carry out the reaction under the same conditions as for the reaction that leads from compound (1-A-A9) to compound (1- A-A1).

[0579] The reaction to lead from a compound (4e) to a compound (4f) is carried out, for example, under the same reaction conditions as for the reaction that leads from the compound (1-A-A1) to the compound (1- D) as shown in reaction scheme 7.

Reaction scheme 12

(4e) (4g) (4h) [0580] where R ¹ , R ^2a , R ^3aa , Xi and n are as indicated above.

[0581] The reaction that takes the compound (4e) to a compound (4g) is carried out, for example, under the same reaction conditions as for the reaction that takes the compound

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351/854 (1-A-A1) to compound (1-A-A7) as shown in reaction scheme 5.

[0582] The reaction that leads from the compound (4g) to a compound (4h) is carried out, for example, under the same reaction conditions as for the reaction that leads from the compound (1-A-A7) to the compound (1b) as shown in reaction scheme 6.

Reaction scheme 13

[0583] where R ¹ and Xi are as indicated above, and R ^2e represents a halogen atom, a C1-6 alkylsulfonyloxy group or a phenylsulfonyloxy group which may have a C1-6 alkyl group as a substituent on the phenyl ring.

[0584] The reaction to take a compound (41) to a compound (3b) is carried out in an appropriate solvent in the presence of a basic compound.

[0585] Any solvent can be used widely here, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type may include polar aprotic solvents, such as DMSO or acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline or liquid paraffin, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, solvents of ether, such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, acetone, ethyl acetate, and mixed solvents thereof.

[0586] The same basic compound as used in a reaction of the compound represented by the general formula (2) above with the compound represented by the general formula (3a) above) can be used here.

[0587] The molar ratio of said basic compound to compound (41) can generally be 1: 1 or greater, preferably between 1: 1 and 5: 1, and more preferably between 1: 1 and 2 : 1.

[0588] The reaction temperature for this reaction is usually 0 ° C to 150 ° C,

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352/854 preferably 0 ° C to 100 ° C, and more preferably 0 ° C to 60 ° C. The reaction time is generally 30 minutes to 48 hours, preferably 1 to 24 hours, and more preferably, 1 to 4 hours.

[0589] The reaction mixture obtained using the above method is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound (3b) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization. Reaction scheme 14

R ¹ kz (CH2) nR ² 0 R1 _R 1 o ( ^CH 2) n * \ cH ₂ ) _n R ² (5) (3f) (6) [0590] where R ¹ , R ^{2 and} n are as indicated above .

[0591] The reaction to take a compound (5) to a compound (3f) is carried out, for example, by treating the compound (5) with trimethylsulfoxonium iodide in an appropriate solvent in the presence of a basic compound.

[0592] Any solvent can be used widely here, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type may include polar aprotic solvents, such as DMSO or acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline or liquid paraffin, ether solvents such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, and mixed solvents thereof.

[0593] Examples of a basic compound can include sodium hydride, sodium amide, metal alcoholates, such as sodium methoxide, sodium ethoxide or potassium ter-butoxide.

[0594] The molar ratio of a basic compound of the type referred to the compound (5) can generally be equal to 1: 1 or greater, preferably between 1: 1 and 3: 1, and more preferably between 1: 1 and 1.5: 1.

[0595] In addition, the molar ratio of trimethylsulfoxonium iodide to compound (5) can generally be equal to 1: 1 or greater, preferably between 1: 1 and 3: 1, and,

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353/854 more preferably, between 1: 1 and 1.5: 1.

[0596] The reaction temperature for this reaction is generally 0 ° C to 80 ° C, preferably 10 ° C to 50 ° C, and more preferably 20 ° C to 35 ° C. The reaction time is generally 1 to 24 hours, preferably 1 to 12 hours, and more preferably, 1 to 4 hours.

[0597] The reaction mixture obtained using the above method is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound (3f) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0598] The reaction to take a compound (6) to the compound (3f) is carried out, for example, by treating the compound (6) with peroxide in an appropriate solvent.

[0599] Any reaction solvent can be used widely here, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type may include water, alcohol solvents such as methanol or ethanol, polar aprotic solvents such as DMF, DMSO or acetonitrile, hydrocarbon solvents such as benzene, toluene, xylene, tetraline, liquid paraffin or cyclohexane , hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, and mixed solvents thereof.

[0600] Examples of peroxide include metachloroperbenzoic acid (mCPBA), perbenzoic acid, peracetic acid and hydrogen peroxide.

[0601] The molar ratio of said peroxide to compound (6) can generally be between 1: 1 and 2: 1, preferably between 1: 1 and 1.5: 1, and more preferably between 1: 1 and 1.3: 1.

[0602] The reaction temperature for this reaction is generally 0 ° C to 80 ° C, preferably 0 ° C to 50 ° C, and more preferably 20 ° C to 35 ° C. The reaction time is generally 10 minutes to 24 hours, preferably 1 to 12 hours, and more preferably, 1 to 8 hours.

[0603] The reaction mixture obtained using the above method is cooled, by

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354/854 example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the compound (3f) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0604] For example, a type of compounds (3f) that is optically active is produced from compound (6) as follows.

[0605] An optically active compound of the type referred to (3f) can be produced by what is called Sharpless epoxidation. This means that the compound can be produced by epoxidation with cumene hydroperoxide or tert-butyl hydroperoxide, in the coexistence of Ti (O-iso-C3H?) 4 and optically active C1-6 alkyl tartrate, such as diethyl tartrate (form D or L) as catalysts, in the above reaction that leads from compound (6) to compound (3f).

[0606] Any solvent can be used widely here, as long as it does not inhibit the reaction. Examples of a solvent of the aforementioned type may include polar aprotic solvents, such as acetonitrile, hydrocarbon solvents, such as benzene, toluene, xylene, tetraline, liquid paraffin or cyclohexane, hydrogenated hydrocarbon solvents, such as methylene chloride, chloroform or dichloroethane, ether solvents, such as THF, dioxane, dipropyl ether, diethyl ether or diglyme, and mixed solvents thereof.

[0607] The molar ratio of cumene hydroperoxide or tert-butyl hydroperoxide to compound (6) can generally be between 0.1: 1 and 2: 1, preferably between 0.1: 1 and 1.5: 1 , and, more preferably, between 0.1: 1 and 1: 1.

[0608] The molar ratio of Ti (O-iso-C3H7) 4 to compound (6) can generally be between 0.1: 1 and 2: 1, preferably between 0.1: 1 and 1.5: 1 , and, more preferably, between 0.1: 1 and 1: 1.

[0609] The molar ratio of optically active C1-6 tartrates (form D or L) to the compound (6) can generally be between 1: 1 and 2: 1, preferably between 1: 1 and 1.5: 1, and , more preferably, between 1: 1 and 1.3: 1.

[0610] The reaction temperature for this reaction is generally -50 ° C to 30 ° C, preferably -20 ° C to 20 ° C, and, more preferably, -20 ° C to 5 ° C. The time of

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The reaction is generally 1 to 48 hours, preferably 4 to 24 hours, and more preferably 4 to 12 hours.

[0611] The compound (5) or (6), in which R ¹ and - (CH2) nR ^2a , together with carbon atoms adjacent to it, are linked together by nitrogen atoms to form a piperidine ring, is converted in the same way as indicated above to a compound (compound (3c)), in which R ¹ and - (CH2) nR ^2a , together with carbon atoms adjacent to it, are linked together via nitrogen atoms to form a piperidine ring , in compound (3f).

[0612] The reaction mixture obtained using the above method is cooled, for example, and then its crude reaction product is separated from it by means of an isolation operation, such as filtration, concentration or extraction. Then, the optically active compound (3f) can be isolated and purified from the reaction mixture by means of a common purification operation, such as column chromatography or recrystallization.

[0613] 2,3-dihydro-6-nitroimidazo [2,1-b] oxazole represented by the compound (1) of the present invention and its intermediates represented by the various reaction formulas above include stereoisomers and optical isomers.

Reaction scheme 15

OR ¹ R ^2a H (5) ° R ¹ ^ \ cH ₂ ) _n OSO ₂ R ^3aa ^^ (CH ₂ ) _n R ^2a (3g) (3h) [0614] where R ^3aa , R ¹ , R ^2a en are as indicated above.

[0615] The reaction to take a compound (3g) to a compound (3h) is carried out, for example, under the same reaction conditions as for the reaction that takes the compound (1-A-A7) to the compound (1b) as shown in reaction scheme 6.

Reaction scheme 16

(E-1) (E-2) (E-3)

Petition 870190039560, of 26/04/2019, p. 364/876

356/854 [0616] where R ¹ , X, are not as indicated above.

[0617] R ^11a represents the group - (W) o — N

N-R ^15a [0618] (wherein W and o are as above, R ^15a represents a C1-C20 alkoxycarbonyl group, with the exception that when W represents C = O group, R ^15a represents an alkoxycarbonyl group CI- e), or the group

N — R ^16a [0619] [0620] (where R ^16a represents a C1-C8 alkoxycarbonyl group). R ^11b represents the group [0621]

R ^11c represents the group - (W) o — N nh \ / or group

[0622]

C8), and [0623] [0624] - (W) o — NN — R ^15b \ / or the group (each of R ^15b and R ^16b representing a C3R ^A cycloalkyl group represents a C3-C8 cycloalkyl group.

The reaction to bring the compound (E-1) to the compound (E-2) can be carried out by hydrolysis of the compound (E-1).

[0625] This hydrolysis reaction can be carried out in an appropriate solvent or without a solvent in the presence of acid or a basic compound. Examples of the solvent used may include water, lower alcohols such as methanol, ethanol, isopropanol or tert-butanol, ketones, such as acetone or methyl ethyl ketone, ethers, such as diethyl ether, dioxane, tetrahydrofuran, monoglyph or diglyme, fatty acids, such as acetic acid or formic acid, esters, such as methyl acetate or ethyl acetate, halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane or carbon tetrachloride, dimethyl sulfoxide, Ν, Ν-dimethylformamide, acid triamide

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357/854 hexamethylphosphoric, and mixed solvents thereof. Examples of acid may include inorganic acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid, and organic acids including formic acid, acetic acid, trifluoroacetic acid or sulfonic acids, such as p-toluenesulfonic acid. Examples of a basic compound can include carbonates, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, and metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide or lithium hydroxide. This reaction is carried out generally at 0 ° C to 200 ° C, and preferably at 0 ° C to 150 ° C, generally for 10 minutes to 30 hours.

[0626] The molar ratio of acidic or basic compound to compound (E-1) can be at least equal to 1: 1, and preferably between 1: 1 and 10: 1. However, it is also possible to use acid in a much larger amount as a reaction solvent.

[0627] After completion of the hydrolysis, the reaction can continue to be carried out in an appropriate solvent in the presence of a basic compound, usually at 0 ° C to 100 ° C, and preferably at room temperature up to 70 ° C, approximately for 1 to 30 minutes, in order to complete the reaction. Here, as a solvent and a basic compound, the solvent and basic compound can be used as follows. Examples of a basic compound of the aforementioned type include: organic bases, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN) , 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO); inorganic bases including carbonates, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, metal hydroxides, such as sodium hydroxide, potassium hydroxide or calcium hydroxide, potassium hydride, sodium hydride, potassium, sodium , sodium amide, and metal alcoholates, such as sodium methylate or sodium ethylate. In addition, examples of a solvent include halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane or carbon tetrachloride, aromatic hydrocarbons, such as benzene, toluene or xylene, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dimethoxy ethane, esters, as acetates methyl, ethyl acetate or

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358/854 isopropyl acetate, alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl celosolve or methyl celosolve, acetonitrile, pyridine, acetone, water, aprotic polar solvents, such as Ν , Ν-dimethylacetamide, N, Ndimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide, and mixed solvents thereof.

[0628] The reaction of the compound (E-2) with the compound (13) is carried out without solvent or in an appropriate solvent, in the presence of a reducing agent.

[0629] Examples of a solvent used here may include water, lower alcohols, such as methanol, ethanol, isopropanol butanol, ter-butanol or ethylene glycol, acetonitrile, fatty acids, such as formic acid, acetic acid or trifluoroacetic acid, ethers, such as ether of diethyl, tetrahydrofuran, dioxane, monoglime or diglyme, aromatic hydrocarbons, such as benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, and mixed solvents thereof. Examples of a reducing agent include formic acid, fatty acid alkali metal salts, such as sodium formate or sodium acetate, and metal hydride reducing agents, such as sodium borohydride, sodium cyanoborohydride, sodium triacetyloxy borohydride, hydride lithium aluminum or a mixture thereof, and catalytic hydrogenation reducing agents, such as palladium black, carbonopalladium, platinum oxide, platinum black or Raney nickel.

[0630] When formic acid is used as a reducing agent, the reaction temperature is generally from room temperature to 200 ° C, and preferably from 50 ° C to 150 ° C. The reaction is carried out for 10 minutes up to 10 hours. It may be preferable to use a much greater amount of formic acid than the compound (E-2).

[0631] When using a hydrogenation reducing agent, the reaction temperature is generally -80 ° C to 100 ° C, and preferably -80 ° C to 70 ° C. The reaction is carried out for 30 minutes to 100 hours. The hydrogenation reducing agent is used with the compound (E-2) in a molar ratio generally between 1: 1 and 20: 1, and preferably between 1: 1 and 6: 1. In particular, when hydride is used lithium aluminum as a reducing agent, it is preferable to use ethers, such as diethyl ether, tetrahydrofuran, dioxane, monoglyme or diglyme, as a solvent, or

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359/854 aromatic hydrocarbons, such as benzene, toluene or xylene. In addition, amines, such as trimethylamine, triethylamine, N-ethyldiisopropylamine can also be added to the reaction. In addition, molecular sieves, such as 3A molecular sieves (MS-3A) or 4A molecular sieves (MS-4A) can also be added.

[0632] When using a catalytic hydrogenation reducing agent, the reaction is carried out in a hydrogen atmosphere, usually from normal atmospheric pressure up to 20 [times] to atmospheric pressure, preferably from normal atmospheric pressure up to 10 [times] to atmospheric pressure, in the presence of a hydrogen supplier, such as formic acid, ammonium formate, cyclohexene or hydrated hydrazine, at a temperature of generally -30 ° C to 100 ° C, and preferably 0 ° C to 60 ° C. The reaction is usually carried out for 1 to 12 hours. It is generally used from 0.1 to 40% by weight, and preferably from 1 to 20% by weight, of the catalytic hydrogenation reducing agent to the compound (E-2).

[0633] The compound (13) is used to the compound (E-2) in a molar ratio generally at least equal to 1: 1, and preferably equal to 1: 1 or much greater.

Reaction scheme 17

[0634] where R ¹ , X, n, m, W and o are as indicated above, R ^14b represents a C1-6 alkoxycarbonyl group, and R ^14Aa is a hydrogen atom, a C1-6 alkoxy group, a group hydroxyl or a phenyl group (phenyl group may have halogen atoms in the phenyl ring).

[0635] The reaction to bring the compound (Eaa 6-1) to the compound (Eaa 5-1) can be carried out under the same conditions as for the reaction that takes the compound (E-1) to the represented compound (E-2) by reaction scheme 16 above.

Reaction scheme 18

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360/854

(Fd-3) [0636] where R ¹ , n and X2 are as indicated above, R ⁵² is a hydrogen atom or C1-6 alkyl group.

[0637] R ^26b represents a halogen atom, a cyano group, an amino group that may have a C1-6 alkyl group as a substituent, an unsubstituted or substituted C1-6 alkyl group, a C1-6 alkoxy group not substituted or substituted by halogen, a C1-6 alkoxycarbonyl group, a carboxyl group, a phenoxy group (with, in the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent), a C1-6 alkyl amino group (with, in the amino group, at least one group selected from one group consisting of a C1-6 alkyl group and a phenyl group (with, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen , I m C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent) can be substituted as a substituent), or a phenyl C1-6 alkoxy group (where, on the phenyl ring, at least one group selected from one group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent).

[0638] p represents an integer from 0 to 4.

[0639] R ^26a represents the -NHR ^26h group (where R ^26h represents a hydrogen atom or a C1-e alkyl group), or the -Wi-NHR ^{26c group} (where W1 is a group

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361/854 C1-6 alkylene, R ^26c represents a hydrogen atom, a C1-6 alkyl group or a phenyl group (with, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent)).

[0640] R ^26d represents the group -N (R ^26e ') R ^26h or the group -Wi-N (R ^26c ) R ^26e .

[0641] R ^26e represents a phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and an alkoxy group C1-6 unsubstituted or substituted by halogen can be substituted as a substituent) or a C1-6 alkyl group.

[0642] R ^26e 'represents a C1-6 alkyl group.

[0643] R ^26f represents a C1-8 alkyl group, and [0644] R ^26g represents the group -N (R ^26h ) CH (R ⁵² ) R ^26f or the group -WiN (R ^26c ) CH (R ⁵² ) R ^26f , provided that the total number of carbon atoms in the underlined portions is not greater than 6.

[0645] The reaction of the compound (Fd-1) with the compound (15) is generally carried out in an appropriate solvent in the presence or absence of a basic compound.

[0646] Examples of an inert solvent used here may include aromatic hydrocarbons, such as benzene, toluene or xylene, ethers, such as diethyl ether, tetrahydrofuran, dioxane, monoglyph or diglyme, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride , lower alcohols, such as methanol, ethanol, isopropanol, butanol, tert-butanol or ethylene glycol, fatty acids, such as acetic acid, esters, such as ethyl acetate or methyl acetate, ketones, such as acetone or methyl ethyl ketone, acetonitrile, pyridine, dimethylsulfoxide , N, Ndimethylformamide or hexamethylphosphoric acid triamide, and mixed solvents thereof. Examples of a basic compound can include carbonates, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide, sodium hydride ,

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362/854 potassium hydride, potassium, sodium, sodium amide, metal alcoholates, such as sodium methylate, sodium ethylate, sodium n-butoxide, organic bases, such as pyridine, imidazole, N-ethylldiisopropylamine, dimethylaminopyridine, triethylamine , trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU) or 1,4 -diazabicycle [2.2.2] octane (DABCO), and mixtures thereof. The compound (15) can be used to the compound (Fd-1) in a molar ratio at least equal to 1: 1, and preferably between 1: 1 and 10: 1. The basic compound can be used with the compound ( Fd-1) in a molar ratio of at least 1: 1, and preferably between 1: 1 and 10: 1. The reaction is carried out generally at 0 ° C to 200 ° C, and preferably at 0 ° C to 150 ° C. The reaction is usually carried out for 5 minutes to 80 hours.

[0647] Alkali metal halides, such as sodium iodide or potassium iodide can be added to the reaction system, or it is also possible to add a phase transfer catalyst. Examples of a phase transfer catalyst of the aforementioned type include: quaternary ammonium salts, in which a group selected from a group consisting of a linear or branched alkyl group containing from 1 to 18 carbon atoms, a phenyl C1-6 alkyl group and, and a phenyl group is substituted, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hydroxide, tetrabutylammonium hydroxide, tetrabutylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium chloride tetrahexylammonium chloride, benzyldimethyloctyl ammonium chloride, methyltriexylammonium chloride, benzyldimethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, tetraethylamethyl chloride; phosphonium salts, such as tetrabutylphosphonium chloride, in which a linear or branched alkyl group containing 1 to 18 carbon atoms is replaced; and pyridinium salts, such as 1-dodecanylpyridinium chloride, with a linear or branched alkyl group containing from 1 to 18 carbon atoms being substituted. The phase transfer catalyst can be used with the compound (Fd-1) in a molar ratio generally between

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363/854

0.1: 1 and 1: 1, and preferably between 0.1: 1 and 0.5: 1.

[0648] The reaction of the compound (Fd-1) with the compound (16) can be carried out under the same conditions as for the reaction above the compound (E-2) with the compound (13) represented by the reaction scheme 16 above.

Reaction scheme 19

[0649] where R ¹ , n, W, X, m, o, R ⁵² and X2 are as indicated above.

[0650] R ^12a represents a C1-6 alkoxycarbonyl group.

[0651] R ^13a represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkanoyl group, a C1-6 alkoxycarbonyl group, a C1-6 phenyl alkyl group (where, in the phenyl ring, at least one from the group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a phenoxy group (where, in the ring phenyl, at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent ) can be substituted, and a C1-6 alkoxyimino group can be substituted by the alkyl moiety), a phenyl group (where, in the phenyl ring, at least one from a group selected from a group consisting of a halogen atom, a group C1-6 alkyl not substituted substituted by halogen, and an unsubstituted or substituted halogen C1-6 alkoxy group may

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364/854 be substituted as a substituent), a benzoyl group (where, in the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted or substituted halogen C1-6 alkoxy group can be substituted as a substituent), a pyridyl group (where, in the pyridine ring, at least one halogen atom can be substituted as a substituent), alkyl phenoxy group C1-6 (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and an unsubstituted C1-6 alkoxy group or substituted by halogen can be substituted as a substituent), or a C6 benzoyl alkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 n alkyl group the unsubstituted or substituted by halogen, and C 1-6 alkoxy group unsubstituted or substituted by halogen may be substituted as a substituent).

[0652] R ^12b represents a C1-6 alkyl group, a C1-6 alkoxycarbonyl group, a C1-6 phenylalkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom , a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a phenoxy group (with, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted or substituted halogen C1-6 alkoxy group can be substituted as a substituent), can be substituted as a substituent, and an alkoxyimino group C1-6 can be substituted by the alkyl portion), a phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group io, and an unsubstituted or substituted halogen C1-6 alkoxy group can be substituted as a substituent), a pyridyl group (where, in the pyridine ring, at least one halogen atom can be substituted as a substituent), one C1-6 alkyl phenoxy group (where, on the phenyl ring, at least one group selected from a group that

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365/854 consists of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent), or a C6 benzoyl alkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be replaced as a substituent).

[0653] R ^12c represents a C1-6 alkanoyl group, or a benzoyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted C1-6 alkyl group or substituted by halogen, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent).

[0654] R ^12d represents a hydrogen atom, a C1-6 alkyl group, a C1-6 phenyl alkyl group (with, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a phenoxy group (with, on the phenyl ring, at least one group selected from a group consisting of an atom halogen, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group can be substituted as a substituent) can be substituted), a phenyl group (where, in the ring phenyl, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, and a phenoxy group (send which, in the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can substituted as a substituent) can be substituted), a phenoxy C1-6 alkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted C1-6 alkyl group or replaced by

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366/854 halogen, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent), or a benzoyl C1-6 alkyl group (with, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent), and the group - (W) oN (R ^13a ) CH (R ⁵² ) R ^12d in the general formula (Ea-5), the total number of carbon atoms in the underlined portion is not greater than 6.

[0655] The reaction to bring the compound (Ea-1) to the compound (Ea-2) can be carried out under the same conditions as for the reaction that takes the compound (E-1) to the compound (E-2) represented by the scheme above 16.

[0656] The reaction of the compound (Ea-2) with the compound (17) can be carried out under the same conditions for the reaction of the compound (Fd-1) with the compound (15) represented by the reaction scheme above 18.

[0657] The reaction of the compound (Ea-2) with the compound (18) is carried out by reacting the compound (Ea-2) with the carboxylic acid of the compound (18) by means of a common amide bond formation reaction. Conditions for a known amide bond formation reaction can easily be applied here. Examples of said amide bonding reaction include (a) mixed acid anhydride method, that is, a method of reacting carboxylic acid (18) with alkyl haloformate to obtain a mixed acid anhydride and reacting the anhydride of mixed acid with amine (Ea-2), (b) active ester method, that is, a method of converting carboxylic acid (18) to active ester, such as phenyl, p-nitrophenyl ester, N acid imide ester -hydroxysuccinic or 1-hydroxybenzotriazole ester, or the active amide, such as benzoxazoline-2-thione, and then react this with amine (Ea-2), (c) carbodiimide method, that is, a method of carrying out the reaction of condensation of carboxylic acid (18) with amine (Ea-2) in the presence of an activator, such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC) or carbonyldiimidazole, and (d) other methods including a method of convert carboxylic acid (18) to carboxylic anhydride using a dehydrator, such as acetic anhydride and reacting the carboxylic anhydride with amine (Ea-2), a method of reacting

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367/854 carboxylic acid ester (18) and lower alcohol with amine (Ea-2) at high pressure and high temperature, and a method of reacting carboxylic acid halide (18), that is, carboxylic acid halide, with amine (Ea-2).

[0658] The mixed acid anhydride used in the mixed acid anhydride method as described above is obtained through a common Schotten-Baumann reaction. The mixed acid anhydride is reacted with amine (Ea-2) generally without undergoing isolation, in order to produce the compound of the present invention represented by the general formula (Ea-4). The above Schotten-Baumann reaction is carried out in the presence of a basic compound. Compounds that are commonly used for the Schotten-Baumann reaction can be used here as basic compounds. Examples of a basic compound of the aforementioned type include: organic bases, such as triethylamine, thmethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopihdine, Nmethylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1 , 8-diazabicyclo [5.4.0] undecene-7 (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO); inorganic bases including carbonates, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, metal hydroxides, such as sodium hydroxide, potassium hydroxide or calcium hydroxide, potassium hydride, sodium hydride, potassium, sodium , sodium amide, and metal alcoholates, such as sodium methylate or sodium ethylate. The reaction is generally carried out at -20 ° C to 100 ° C, and preferably 0 ° C to 50 ° C. The reaction time is generally 5 minutes to 10 hours, and preferably 5 minutes to 2 hours. The reaction of the mixed acid anhydride obtained with amine (Ea-2) is generally carried out at -20 ° C to 150 ° C, and preferably from 10 ° C to 50 ° C. The reaction time is generally 5 minutes to 10 hours, and preferably 5 minutes to 5 hours. The mixed acid anhydride method is generally carried out in a solvent. Any solvent that is commonly used for the mixed acid anhydride method can be used here. Examples of a solvent of the aforementioned type include halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane or carbon tetrachloride, aromatic hydrocarbons, such as benzene, toluene or xylene, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dimethoxyethane, esters, as acetate

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368/854 methyl, ethyl acetate or isopropyl acetate, polar aprotic solvents, such as Ν, Ν-dimethylacetamide, Ν, Ν-dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide, and mixed solvents thereof. Examples of alkyl haloformate used for the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. The molar ratio between carboxylic acid (18), alkyl haloformate and amine (Ea-2) can generally be equal to 1: 1. Each of alkyl haloformate and carboxylic acid (18) can also be used with amine (Ea- 2) in the molar range between 1: 1 and 1.5: 1.

[0659] Method (c) above which involves the condensation reaction in the presence of the above activator can be carried out in an appropriate solvent in the presence or absence of a basic compound. As a solvent and a basic compound used here, it is possible to use any solvent used in a carboxylic acid halide reaction with amine (Ea-2) described above in (d) Other methods'. The molar ratio of the activator to the compound (Ea-2) can be at least equal to 1: 1, and preferably between 1: 1 and 5: 1. When using WSC as an activator, the reaction proceeds advantageously if 1-hydroxybenzotriazole is added to the reaction system. The reaction is carried out generally at -20 ° C to 180 ° C, and preferably from 0 ° C to 150 ° C. The reaction time is usually 5 minutes to 90 hours.

[0660] When the method of reacting carboxylic acid halide with amine (Ea-2) is adopted from (d) Other methods' described above, the reaction is carried out in the presence of a basic compound in an appropriate solvent. Known basic compounds can be used widely here. For example, any basic compound used in the Schotten-Baumann reaction above can be used. Examples of the solvent used may include alcohols, such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl celosolve or methyl celosolve, acetonitrile, pyridine, acetone, water, and also solvents used for the method of the mixed acid anhydride above. The molar ratio of amine (Ea-2) to carboxylic acid halide is not particularly limited, but can be advantageously selected over a wide range. The molar ratio of these compounds can be

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369/854 generally at least equal to 1: 1, and preferably between 1: 1 and 1: 5. The reaction is carried out generally at -20 ° C to 180 ° C, and preferably 0 ° C to 150 ° C. The reaction time is usually 5 minutes to 50 hours.

[0661] The amide bond formation reaction represented by reaction scheme 19 above can also be carried out by reacting carboxylic acid (18) with amine (Ea-2) in the presence of a phosphorus condensing agent, such as chloride diphenylphosphine, phenyl-N-phenyl phosphoramide hydrochloride, diethyl chlorophosphate, diethyl cyanophosphate, diphenyl azide phosphate, or phosphine bis (2-oxo-3oxazolidinyl) chloride.

[0662] This reaction is carried out in the presence of a solvent and a basic compound that are used for the above method of reacting carboxylic acid halide with amine (Ea-2), usually at -20 ° C to 150 ° C, and preferably at 0 ° C to 100 ° C. The reaction time is usually 5 minutes to 30 hours. Each of condensing agent and carboxylic acid (18) is used with amine (Ea-2) in a molar ratio at least equal to 1: 1, and preferably between 1: 1 and 2: 1.

[0663] The reaction of the compound (Ea-2) with the compound (19) can be carried out under the same conditions as for the reaction of the compound (E-2) with the compound (13) represented by the reaction scheme above 16.

Reaction scheme 20

[0664] where R ¹ , n, R ⁵² , p, Wi and X2 are as indicated above.

[0665] R ^19a represents a group represented by each of (F1) to (F11).

[0666] R ⁵³ represents a phenoxy group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a group

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370/854 C1-6 alkyl unsubstituted or substituted by halogen, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent), a halogen atom, an unsubstituted or substituted C1-6 alkyl group halogen, a C1-6 alkoxy group unsubstituted or substituted by halogen, an amino group that may have, as a substituent, a group selected from a group consisting of a C1-6 alkyl group and a phenyl C1-6 alkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent), a piperazinyl group (where, on the piperazine ring, at least one group selected from a group consisting of a phenyl C 1-6 alkyl group (where, on the phenyl ring, at least a group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen and a C1-6 alkoxy group unsubstituted or substituted by halogen) can be substituted as a substituent or a piperidinyl group (where, in the piperidine ring, at least one amino group can be substituted, as a substituent, and in the amino group, at least one group selected from a group consisting of a phenyl group (with, in the phenyl ring, at least a group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent) and an alkyl group C1-6 can be replaced).

[0667] R ⁵⁴ represents a phenyl C1-6 alkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an unsubstituted or halogen-substituted C1-6 alkoxy group can be substituted as a substituent).

[0668] R ⁵⁵ represents a phenyl C1-6 alkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group

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371/854

C1-6 unsubstituted or substituted by halogen can be substituted as a substituent), or phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent), and [0669] the total number of carbon atoms of the CH (R ⁵² ) R ^{55 group} in the formula overall (F3-3) is not greater than 6.

[0670] The reaction of the compound (F3-1) with the compound (20) can be carried out under the same conditions as for the reaction of the compound (Fd-1) with the compound (15) represented by the reaction scheme above 18.

[0671] The reaction of the compound (F3-1) with the compound (21) can be carried out under the same conditions as for the reaction of the compound (E-2) with the compound (13) represented by the reaction scheme above 16.

Reaction scheme 21

H ₂ NN (R ⁴⁷ ) R ⁴⁸

[0672] where R ¹ , η, X, R ⁴⁷ , R ⁴⁸ and m are as indicated above.

[0673] The reaction of the compound (27) with the compound (E18-1) can be carried out in an appropriate inert solvent in the presence or absence of a basic compound.

[0674] Examples of the basic compound used may include basic inorganic compounds, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium carbonate, alkali metal salts of fatty acid, such as sodium acetate, and organic bases, such as piperidine, triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine,

1,5-diazabicycles [4,3,0] nonene-5 (DBN), 1,8-diazabicycles [5,4,0] undecene-7 (DBU) or 1,4-diazabicycles [2.2.2] octane ( DABCO). Any inert solvent can be used, as long as it does not affect the reaction. Examples of a solvent of the aforementioned type include water, aromatic hydrocarbons, such as benzene, toluene or xylene, ethers, such as

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372/854 diethyl, tetrahydrofuran, dioxane, monoglyph or diglyme, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, lower alcohols, such as methanol, ethanol, isopropanol, butanol, ter-butanol or ethylene glycol, fatty acids, such as acetic acid, esters, such as ethyl acetate or methyl acetate, ketones, such as acetone or methyl ethyl ketone, acetonitrile, pyridine, dimethyl sulfoxide, Ν, Ν-dimethylformamide, hexamethylphosphoric acid triamide, and mixed solvents thereof. The molar ratio of the compound (27) to the compound (E181) can generally be at least equal to 1: 1, and preferably between 1: 1 and 5: 1. The reaction temperature is generally from room temperature to 200 ° C, and preferably room temperature up to 150 ° C. The reaction time is usually 5 minutes to 30 hours.

Reaction scheme 22

O

R ^47c CR ⁵² (29)

[0675] where R ¹ , η, X, m, X2 and R ⁵² are as indicated above.

[0676] R ^47a represents a hydrogen atom.

[0677] R ^48a represents a hydrogen atom, a C1-6 alkyl group, a phenyl group (with, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1- alkyl group 6 unsubstituted or substituted by halogen, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent), or a pyridyl group (with, in the pyridine ring, at least unsubstituted C1-6 alkyl group or substituted by halogen can be substituted as a substituent).

[0678] R ^47b represents a C1-8 alkyl group; a phenyl group (and in the ring

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373/854 phenyl, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent); or a pyridyl group (where, on the pyridine ring, at least C1-6 alkyl group unsubstituted or substituted by halogen can be substituted as a substituent), and [0679] R ^47c represents a hydrogen atom or a C1- alkyl group 6, since, in the group -CH = NN (R ^48a ) CH (R ⁵² ) R ^47c in the general formula (Ea 18-5), the total number of carbon atoms in the underlined portion is not greater than 6.

[0680] The reaction of the compound (E18-3) with the compound (28) can be carried out under the same conditions as for the reaction of the compound (Fd-1) with the compound (15) represented by the reaction scheme above 18.

[0681] The reaction of the compound (E18-3) with the compound (29) can be carried out under the same conditions as for the reaction of the compound (E-2) with the compound (13) represented by the reaction scheme above 16.

Reaction scheme 23

[0682] where R ¹ , η, X, m, W and o are as indicated above.

[0683] each of R ^14Ab and R ^14c represents a C1-6 alkoxy group.

[0684] The reaction to bring the compound (Eaa 17-6) to the compound (Eaa 17-7) can be carried out under the same conditions as for the reaction to take the compound (E-1) to the represented compound (E-2) by the above reaction scheme 16.

Reaction scheme 24

[0685] where R ¹ , η, X, m, W, o and R ^14Aa are as indicated above.

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374/854 [0686] the dashed line on the piperidine ring represents that the bond can be a double bond, and when the dashed line represents a double bond, this means that the hydroxyl group is substituted.

[0687] R ⁵⁷ represents a phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, a C1 alkoxy group -6 unsubstituted or substituted by halogen, a C1-C4 alkylenedioxy group, a C1-alkoxycarbonyl group, a cyano group, a C2-C6 alkylenyl group, a nitro group, a phenyl group, an amino group that may have, as a substituent, a group selected from a group consisting of a phenyl group, a C1-6 alkyl group, a carbamoyl group and a C1-6 alkanoyl group, a C1-6 alkyl group substituted by C1-6 alkanoyl, a hydroxyl group , a C1-6 alkyl group substituted by C1-6 alkoxycarbonyl, phenyl C1-6 alkyl group, a C1-6 alkanoyl group, a C1-6 alkylthio group, a 1,2,4-triazolyl group, an isoxazolyl group, a imidazolyl group, a benzothiazolyl group, a 2H-benzotriazolyl group, a pyrrolyl group, a benzoxazolyl, a piperazinyl group (where, in the piperazine ring, at least one group selected from a group consisting of a C1-6 alkoxycarbonyl group and a phenyl C1-6 alkyl group (with, at the phenyl ring, at least one of group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent) a substituent), a piperidine group (where, in the piperidine ring, at least one amino group can be substituted as a substituent, and in the amino group, at least one group selected from a group consisting of a C1-6 alkyl group and a phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group not subs substituted or substituted by halogen can be substituted as a substituent) can be substituted as a substituent) and a carbamoyl group can be substituted as a substituent).

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375/854 [0688] The reaction of the compound (Eaa 4-1) with the compound (31) can be carried out in an appropriate solvent in the presence of a condensing agent.

[0689] Here, you can use the solvent indicated below. Examples of a solvent of the aforementioned type include halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane or carbon tetrachloride, aromatic hydrocarbons, such as benzene, toluene or xylene, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dimethoxyethane, esters, as methyl acetate, ethyl acetate or isopropyl acetate, alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl celosolve or methyl celosolve, acetonitrile, pyridine, acetone, water, solvents aprotic polar, such as Ν, Ν-dimethylacetamide, N, Ndimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide, and mixed solvents thereof.

[0690] Examples of the condensing agent used here may include azocarboxylates, such as diethyl azodicarboxylate or tert-butyl azodicarboxylate, and mixtures of phosphorus compound, such as triphenylphosphine or supported triphenylphosphine polymer. This reaction is carried out generally at 0 ° C to 200 ° C, and preferably at 0 ° C to 150 ° C. The reaction is usually carried out for 1 to 10 hours. The molar ratio of the condensing agent to the compound (Eaa 4-1) can be at least equal to 1: 1, and preferably between 1: 1 and 3: 1. The molar ratio of the compound (31) to the compound (Eaa 4-1) can be at least 1: 1, and preferably between 1: 1 and 2: 1.

Reaction scheme 25

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376/854

[0691] where R ¹ , η, X, m, X2 and R ⁵² are as indicated above.

[0692] R ^46a represents a C1-6 alkoxycarbonyl group.

[0693] R ^46b represents a phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and an alkoxy group C1-6 unsubstituted or substituted by halogen can be substituted as a substituent), a phenyl C1-6 alkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a group C1-6 alkyl unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent), a phenyl C1-6 alkoxycarbonyl group (with, in the phenyl ring, at least one group selected from a group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a su substituting), or a C1-6 alkoxycarbonyl group.

[0694] R ^46c represents a phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and an alkoxy group C1-6 unsubstituted or substituted by halogen can be substituted as a substituent),

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377/854 or a phenyl C1-6 alkyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent), and [0695] R ^46d represents a phenyl group (with, on the phenyl ring, at least one group selected from a group consisting of an atom halogen, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group may be substituted as a substituent), or a C1-6 alkyl group.

[0696] The reaction to take the compound (E14-1) to the compound (E14-2) can be carried out under the same conditions as for the reaction to take the compound (E-1) to the compound (E-2) represented by the scheme above 16.

[0697] The reaction of the compound (E14-2) with the compound (34) can be carried out under the same conditions as for the reaction of the compound (Fd-1) with the compound (15) represented by the reaction scheme above 18.

[0698] The reaction of the compound (E14-2) with the compound (33) can be carried out under the same conditions as for the reaction of the compound (E-2) with the compound (13) represented by the reaction scheme above 16.

[0699] The reaction of the compound (E14-2) with the compound (32) can be carried out in an appropriate solvent in the presence of a condensing agent. Any solvent can be used here, which is used in the method of reactions of the compound (Eaa 4-1) with the compound (31) represented by the above reaction scheme 24. N, N'carbonildiimidazole is an example of the condensing agent used here. Each of compound (32) and condensing agent is used with the compound (E14-2) in a molar ratio at least equal to 1: 1, and preferably between 1: 1 and 2: 1. This reaction is carried out generally at 0 ° C to 150 ° C, and preferably 0 ° C to 100 ° C, for approximately 1 to 30 hours.

Reaction scheme 26

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378/854 o ₂ n

(Fca12-1)

(Fca12-2)

0 ₂ N

R ⁵⁸ OH (36)

(Fca12-3) [0700] where R ¹ , neo are as indicated above.

[0701] R ^24a and R ^25a form a piperazine ring through a nitrogen atom adjacent to it, and the piperazine ring, which R ^24a and R ^25a form, may have, as a substituent, at least one substituent described as above, for the 5- to 6-membered saturated heterocycle substituents that R ²⁴ and R ²⁵ form through nitrogen atoms adjacent to it, and the piperazine ring that R ^24a and R ^25a form has a C1-6 alkoxycarbonyl group on the nitrogen in the piperazine ring.

[0702] R ⁵⁸ represents a phenyl group (where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and an alkoxy group C1-6 not substituted or substituted by halogen can be substituted as a substituent). [0703] R ^24b and R ^25b form a piperazine ring by means of a nitrogen atom adjacent to it, and the piperazine ring, which R ^24b and R ^25b form, may have, as a substituent at least one substituent described as above, for the 5- to 6-membered saturated heterocycle substituent that R ²⁴ and R ²⁵ form through nitrogen atoms adjacent to it, and the piperazine ring that R ^24b and R ^25b form has a hydrogen atom in the nitrogen atom in the piperazine ring, and [0704] R ^24c and R ^25c form a piperazine ring by means of a nitrogen atom adjacent to it, and the piperazine ring, which R ^24c and R ^25c form, may have, as a substituent, at least one substituent described as above, for the

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379/854 substituents of the 5- to 6-membered saturated heterocycle that R ²⁴ and R ²⁵ form through nitrogen atoms adjacent to it, and the piperazine ring that R ^24c and R ^25c form has a phenyl C 1-6 alkoxycarbonyl group ( where, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen may substituted as a substituent) on the nitrogen atom in the piperazine ring.

[0705] The reaction to take the compound (Fca 12-1) to the compound (Fca 12-2) can be carried out under the same conditions as for the reaction to take the compound (E-1) to the represented compound (E-2) by the above reaction scheme 16.

[0706] The reaction of the compound (Fca 12-2) with the compound (36) can be carried out under the same conditions as for the reaction of the compound (E14-2) with the compound (32) represented by the above reaction scheme 25.

Reaction scheme 27

R ^46a OH (37)

------- ^{(CH2) n_} o ₂ n ^ n (Fd-39-3) [0707] where R ^{1 and} n are as indicated above.

[0708] R ^45a represents a Ci-e alkoxycarbonyl group, and [0709] R ^46a represents a phenyl group (with, on the phenyl ring, at least one group selected from a group consisting of a halogen atom, an alkyl group C1-6 unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen can be substituted as a substituent).

[0710] The reaction to bring the compound (Fd-39-1) to the compound (Fd-39-2) can be carried out under the same conditions as for the reaction to bring the compound (E-1) to the

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380/854 compound (E-2) represented by the above reaction scheme 16.

[0711] The reaction of the compound (Fd-39-2) with the compound (37) can be carried out under the same conditions as for the reaction of the compound (E14-2) with the compound (32) represented by the reaction scheme above 25.

[0712] The compound of the present invention includes a pharmaceutically acceptable salt. Examples of a salt of the aforementioned type include inorganic salts, such as hydrochloride, hydrobromide, nitrate, sulfate or phosphate, and organic salts, such as methanesulfonate, p-toluenesulfonate, acetate, citrate, tartrate, maleate, fumarate, malate or lactate.

[0713] Next, a medicinal preparation containing the compound of the present invention as an active ingredient will be explained.

[0714] The above medicinal preparation is obtained by preparing the compound of the present invention in the form of a common medicinal preparation. It is prepared using diluents, or commonly used excipients, as a filler, extender, ligand, wetting agent, disintegrator, surfactant or lubricant.

[0715] A medicinal preparation of the aforementioned type can be selected from several forms, depending on the therapeutic purposes. Typical examples of a preparation form include a tablet, pills, powder, liquid, suspension, emulsion, granule, capsule, suppository, and injection (liquid, suspension, etc.) [0716] Known vehicles can be widely used in the preparation of the preparation medicinal in a tablet form. Examples of such a vehicle include excipients, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or crystalline cellulose; ligands, such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate or polyvinylpyrrolidone; disintegrators, such as dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch or lactose; disintegration controllers, such as sucrose, stearin, cocoa butter or hydrogenated oil; absorption enhancers, such as ammonium base

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381/854 quaternary or sodium lauryl sulfate, humectants, such as glycerin or starch, adsorbents, such as starch, lactose, kaolin, bentonite or colloidal silica, and lubricants, such as purified talc, stearate, boric acid powder or polyethylene glycol.

[0717] In addition, tablets of the aforementioned type can be prepared as tablets with usual tablet coating, such as a sugar coated tablet, gelatin coated tablet, enteric coated tablet, film coated tablet, double coated tablet, or multiple tablet. coatings.

[0718] Known vehicles can be widely used in the manufacture of medicinal preparation in a pill form. Examples of a vehicle of the aforementioned type include excipients, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin or talc, ligands, such as powdered gum arabic, powdered tragacanth, gelatin or ethanol, and disintegrants, such as laminaran or agar.

[0719] Known vehicles can be widely used in the manufacture of the medicinal preparation in a suppository form. Examples of such a vehicle include polyethylene glycol, cocoa butter, higher alcohol, higher alcohol esters, gelatin, and semi-synthetic glyceride.

[0720] In a case where the medicinal preparation is formulated as an injection, as a liquid, emulsion or suspension, these solutions are preferably sterilized and prepared in order to be isotonic with blood. Known diluents can be widely used in the manufacture of the medicinal preparation in said liquid, emulsion or suspension form. Examples of a diluent of the aforementioned type include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In addition, if the medicinal preparation is used as an injection, it is possible to add a certain amount of common salts, glucose or glycerin to the medicinal preparation sufficient to prepare an isotonic solution. Otherwise, a usual solubilizing agent, buffer, soothing agent or the like can also be added to the medicinal preparation. In addition, it is also possible to add a coloring agent, preservative, perfume, flavoring, sweetening agent or other pharmaceuticals, if necessary.

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382/854 [0721] The amount of the compound of the present invention contained in the medicinal preparation is not particularly limited, but can be appropriately selected from a wide range. Generally, from 1 to 70% by weight of the compound of the present invention are preferably contained in the medicinal preparation.

[0722] The method of administering the medicinal preparation of the present invention is not particularly limited. It is administered depending on various forms of preparation, the patient's age, sex, disease conditions, or other conditions. For example, where the medicinal preparation takes the form of a tablet, pills, liquid, suspension, emulsion, granule or capsule, it is administered orally. In the case of an injection, it can be administered intravenously, simply or in combination with a common auxiliary fluid, such as glucose or amino acid. In addition, if necessary, it can be administered simple intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of a suppository, it can be administered intrarectally.

[0723] The dose of the above medicinal preparation can be selected appropriately depending on the use, the age of the patient, the sex, the stage of the disease, or other conditions. Generally, 0.01 to 100 mg, preferably 0.1 to 50 mg per kg of body weight of the medicinal preparation, is administered once or divided into several times a day.

[0724] As the above dose is changed depending on several conditions, a lower dose than the above range may be sufficient in some cases, or a higher dose than the above range may be necessary in other cases.

[0725] The compound of the present invention has a specific effect against Micobacterium tuberculosis, such as acid-resistant bacteria (Micobacterium, atypical acid-resistant bacteria). The compound of the present invention has an excellent effect against multiple drug resistant Mycobacterium tuberculosis. The compound of the present invention has an antimicrobial action against anaerobic bacteria.

[0726] The compound of the present invention not only exhibits the activities described above in vitro, but also expresses the above activities in oral administration.

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383/854 [0727] The compound of the present invention does not induce diarrhea, which is induced by known antimicrobial agents having a broad spectrum for common bacteria, such as Gram-positive or Gram-negative bacteria. Additionally, it has fewer adverse reactions than existing agents. Thus, it can constitute a medicinal preparation that can be administered over an extended period.

[0728] The compound of the present invention can be well distributed in the tissues of the lung, the main organ infected by acid-resistant bacteria, and has properties such as prolonged efficacy or excellent safety. Thus, a high therapeutic effect can be expected from the compound.

[0729] When compared to existing antituberculous agents, the compound of the present invention has a strong bactericidal action even against cytozoic bacteria, such as Micobacterium tuberculosis present in a human macrophage. Thus, it allows a reduction in the rate of reoccurrence of tuberculosis and short-term chemotherapy. It is therefore expected that the compound of the present invention will also be used as a major preventive agent administered for mixed HIV and tuberculosis infection, which is considered to be a serious problem.

EXAMPLES [0730] Formulation Example, Reference Examples, Examples and Test Example will be described below.

Formulation Example 1 [0731] 100 g of a compound of the invention, 40 g of Avicel (trade name, manufactured by Asahi Kasei Corporation), 30 g of corn starch and 2 g of magnesium stearate were mixed and ground, and then formed in tablets with the aid of a pestle, with sugarcoat R10 mm sugar coating.

[0732] A film coating agent containing 10 g of TC-5 (trade name, hydroxypropyl methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.), 3 g of polyethylene glycol-6000, 40 g of castor oil and an appropriate amount of ethanol was used to coat the obtained tablets, producing a tablet coated with

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384/854 film showing the composition described above.

Reference Example 1

Preparation of benzyl 4- (2-oxopropyl) piperazine-1-carboxylate [0733] Potassium carbonate (1.27 g, 9.22 mmol), N-ethyldiisopropylamine (0.80 ml, 4.61 mmol), and chloroacetone (1.22 ml, 13.83 mmol) was added to a solution of benzyl piperazine-1-carboxylate (2.03 g, 90.22 mmol) in acetonitrile (20 ml), and the mixture was heated to reflux for 2 hours. Insoluble substances were removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving benzyl 4- (2oxopropyl) piperazine-1-carboxylate (2.24 g, 88% yield) as a light yellow oil.

[0734] ¹ H NMR (CDCb) δ ppm:

[0735] 2.15 (3H, s), 2.35-2.50 (4H, m), 3.21 (2H, s), 3.50 - 3.62 (4H, m), 5.13 (2H,

s), 7.27-7.42 (5H, m).

Reference Example 2

Preparation of ter-butyl 4- (3-oxobutyl) piperazine-1-carboxylate [0736] A solution of ter-butyl piperazino-1-carboxylate (6 g, 32.3 mmol) in THF (50 ml) was added gradually by dripping to a solution of methyl vinyl ketone (2.3 g, 32.9 mmol) in THF (25 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving 4 (3-oxobutyl) piperazine-1-carboxylate -butyl (7.2 g, 87% yield) as a light yellow oil.

[0737] ¹ H NMR (CDCb) δ ppm:

[0738] 1.46 (9H, s), 2.17 (3H, s), 2.30 - 2.42 (4H, m), 2.53 - 2.70 (4H, m), 3.33 -

3.47 (4H, m).

[0739] Using corresponding starting materials, compounds of Reference Examples 3 to 10 were prepared in the same manner as described in

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385/854

Reference Example 1.

Reference Example 3

- [4- (4-trifluoromethylphenyl) piperazin-1-yl] propan-2-one [0740] 99% yield [0741] ¹ H NMR (CDCb) δ ppm:

[0742] 2.18 (3H, s), 2.63 - 2.68 (4H, m), 3.27 (2H, s), 3.30 - 3.45 (4H, m), 6.92 (2H, d, J = 8.7 Hz), 7.48 (2H, d, J = 8.7 Hz).

Reference Example 4

- (4-phenylpiperazin-1-yl) propan-2-one [0743] 95% yield [0744] ¹ H NMR (CDCb) δ ppm:

[0745] 2.19 (3H, s), 2.65 - 2.70 (4H, m), 3.27 - 3.32 (6H, m), 6.97 - 7.01 (2H, m) ,

7.24 - 7.31 (1H, m), 7.37 - 7.43 (2H, m).

Reference Example 5

- [4- (4-chlorophenyl) piperazin-1-yl] propan-2-one [0746] 99% yield [0747] ¹ H NMR (CDCb) δ ppm:

[0748] 2.17 (3H, s), 2.63 - 2.67 (4H, m), 3.18 - 3.23 (4H, m), 3.26 (2H, s), 6.80 6.87 (2H, m), 7.17-7.23 (2H, m).

Reference Example 6

- [4- (4-trifluoromethoxyphenyl) piperazin-1-yl] propan-2-one [0749] 100% yield [0750] ¹ H NMR (CDCb) δ ppm:

[0751] 2.18 (3H, s), 2.63 - 2.68 (4H, m), 3.20 - 3.25 (4H, m), 3.26 (2H, s), 6.85 6.92 (2H, m), 7.09 - 7.13 (2H, m).

Reference Example 7

- [4- (2-pyridyl) piperazin-1-yl] propan-2-one [0752] 97% yield [0753] ¹ H NMR (CDCb) δ ppm:

[0754] 2.19 (3H, s), 2.58 - 2.63 (4H, m), 3.25 (2H, s), 3.57 - 3.62 (4H, m), 6.60 Petition 870190039560, of 26/04/2019, p. 394/876

386/854

6.66 (2H, m), 7.44-7.51 (1H, m), 8.17 - 8.20 (1H, m).

Reference Example 8

- [4- (2-pyrim idyl) piperazin-1-yl] propan-2-one [0755] 88% yield [0756] ¹ H NMR (CDCb) δ ppm:

[0757] 2.19 (3H, s), 2.53-2.57 (4H, m), 3.25 (2H, s), 3.86 - 3.90 (4H, m), 6.49 (1H, t, J = 4.8 Hz), 8.30 (2H, d, J = 4.8 Hz).

Reference Example 9

N-methyl- [1- (2-oxopropyl) piperidin-4-yl] ter-butyl carbamate [0758] 79% yield [0759] ¹ H NMR (CDCb) δ ppm:

[0760] 1.46 (9H, s), 1.57 - 1.63 (2H, m), 1.70 - 1.91 (2H, m), 2.04-2.18 (2H, m) ,

2.14 (3H, s), 2.71 - 2.74 (1H, m), 2.74 (3H, s), 2.90-2.95 (2H, m), 3.19 (2H, s). Reference Example 10

Tert-butyl 4- (2-oxopropyl) homopiperazine-1-carboxylate [0761] 58% yield [0762] ¹ H NMR (CDCb) δ ppm:

[0763] 1.46 (9H, s), 1.75 -1.93 (2H, m), 2.14 (3H, s), 2.64 - 2.76 (4H, m), 3.32 (2H,

s), 3.38-3.58 (4H, m).

Reference Example 11

Preparation of 1- (4-trifluoromethylbenzoyl) -4-hydroxypiperidine [0764] 4- (Trifluoromethyl) benzoyl chloride (1.5 ml, 9.89 mmol) was added to a solution of 4-hydroxypiperidine (1 g, 9, 89 mmol) and triethylamine (1.7 ml, 11.9 mmol) in methylene chloride (20 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / acetone = 2/1) giving 1- (4-trifluoromethylbenzoyl) -4-hydroxypipendin (2.07 g, 77% yield) as a colorless crystalline powder.

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387/854 [0765] ¹ H NMR (CDCh) δ ppm:

[0766] 1.36 - 2.07 (4H, m), 3.07 - 3.70 (3H, m), 3.91 - 4.32 (2H, m), 7.51 (2H, d, J = 8.0 Hz), 7.68 (2H, d, J = 8.0 Hz).

[0767] Using a corresponding starting material, a compound of Reference Example 12 was prepared in the same manner as described in Reference Example 11.

Reference Example 12

1- (4-trifluoromethoxybenzoyl) -4-hydroxypipendin [0768] a colorless crystalline powder, 100% yield [0769] ¹ H NMR (CDCl3) δ ppm:

[0770] 1.34 - 2.07 (4H, m), 3.09 - 3.80 (3H, m), 3.91 - 4.32 (2H, m), 7.25 (2H, d, J = 7.9 Hz), 7.45 (2H, d, J = 7.9 Hz).

Reference Example 13

Preparation of 1 - [2- (tetrahydropyran-2-yloxy) ethyl] -4- (4-trifluoromethylphenoxy) piperidine [0771] A mixture of 4- (4-trifluoromethylphenoxy) pipendin (1.87 g, 7.63 mmol) , 2 (2-bromoethoxy) tetrahydropyran (1.75 g, 8.4 mmol), potassium carbonate (1.16 g, 8.38 mmol), sodium iodide (1.2 g, 8.01 mmol) in DMF (30 ml) was stirred at 100 ° C for 1 hour. The reaction mixture was allowed to return to room temperature, poured into water and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 50/1) giving 1 [2- (tetrahydropyran-2-yloxy) ethyl] -4- (4-trifluoromethylphenoxy) piperidine (1 , 69 g, 59% yield) as a colorless oil.

[0772] ¹ H NMR (CDCl3) δ ppm:

[0773] 1.39 - 2.12 (10H, m), 2.36 - 2.53 (2H, m), 2.68 (2H, t, J = 6.1 Hz), 2.71 2, 92 (2H, m), 3.43 - 3.63 (2H, m), 3.78 - 3.94 (2H, m), 4.31 - 4.47 (1H, m), 4.57 - 4.67 (1H, m), 6.96 (2H, d, J = 8.7 Hz), 7.52 (2H, d, J = 8.7 Hz).

Reference Example 14

Preparation of 2- [4- (4-trifluoromethylphenoxy) piperidin-1-yl] ethanol

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388/854 [0774] A mixture of 1 - [2- (tetrahydropyran-2-yloxy) ethyl] -4- (4trifluoromethylphenoxy) piperidine (1.69 g, 4.53 mmol) prepared in Reference Example 13 and p- pyridinium toluenesulfonate (114 mg, 0.45 mmol) in ethanol (50 ml) was stirred at 60 to 70 ° C for 6 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving 2- [4- (4-trifluoromethylphenoxy) piperidin-1-yl] ethanol (1.19 g, yield 91%) as a colorless oil.

[0775] ¹ H NMR (CDCb) δ ppm:

[0776] 1.73 -2.10 (4H, m), 2.31 -2.47 (2H, m), 2.58 (2H, t, J = 5.5 Hz), 2.69-3 .00 (3H, m), 3.63 (2H, t, J = 5.5 Hz), 4.33 - 4.48 (1H, m), 6.95 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz).

Reference Example 15

Preparation of 2- [2- (4-trifluoromethylphenoxy) ethoxy] tetrahydropyran [0777] A mixture of 4-hydroxybenzotrifluoride (2.08 g, 12.83 mmol), 2- (2 bromoethoxy) tetrahydropyran (3 g, 14.11 mmol ), potassium carbonate (1.95 g, 14.11 mmol), and sodium iodide (2 g, 13.47 mmol) in DMF (15 ml) was stirred at 100 ° C for 3 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving 2- [2- (4trifluoromethylphenoxy) ethoxy] tetrahydropyran (2.47 g, 66% yield) as a colorless oil.

[0778] ¹ H NMR (CDCb) δ ppm:

[0779] 1.41 - 1.90 (6H, m), 3.45 - 3.66 (1H, m), 3.76 - 3.96 (2H, m), 4.02 - 4.24 ( 3H,

m), 4.63 - 4.76 (1H, m), 6.98 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz).

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389/854

Reference Example 16

Preparation of 2- (4-trifluoromethylphenoxy) ethanol [0780] Using 2- [2- (4-trifluoromethylphenoxy) ethoxy] tetrahydropyran (2.47 g, 8.51 mmol) prepared in Reference Example 15, 2- (4- trifluoromethylphenoxy) ethanol (1.32 g, 79% yield) as a colorless crystalline powder was prepared in the same manner as described in Reference Example 14.

[0781] ¹ H NMR (CDCb) δ ppm:

[0782] 3.88 - 4.14 (4H, m), 6.98 (2H, d, J = 8.6 Hz), 7.55 (2H, d, J = 8.6 Hz).

Reference Example 17

Preparation of 1 - [2- (tetrahydropyran-2-yloxy) ethyl] -4- (4-trifluoromethoxyphenyl) -1,2,3,6tetrahydropyridine [0783] Using 4- (4-trifluoromethoxyphenyl) -1,2 monohydrochloride, 3,6 tetrahydropyridine (680 mg, 2.43 mmol) and 2- (2-bromoethoxy) tetrahydropyran (610 mg, 2.92 mmol), 1 - [2- (tetrahydropyran-2-yloxy) ethyl] -4- (4 -trifluoromethoxyphenyl 1) -1,2,3,6tetrahydropyridine (425 mg, 47% yield) as a light brown oil was prepared in the same manner as described in Reference Example 15.

[0784] ¹ H NMR (CDCb) δ ppm:

[0785] 1.41 - 1.92 (6H, m), 2.45 - 2.59 (2H, m), 2.67 - 2.86 (4H, m), 3.18 - 3.31 ( 2H,

m), 3.43 - 3.65 (2H, m), 3.80 - 4.00 (2H, m), 4.55 - 4.65 (1H, m), 5.98 - 6.10 ( 1H, m), 7.15 (2H, dd, J = 2.1 Hz, 8.8 Hz), 7.38 (2H, dd, J = 2.1 Hz, 8.8 Hz).

Reference Example 18

Preparation of 2- [4- (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridin-1-yl] ethanol [0786] Using 1 - [2- (tetrahydropyran-2-yloxy) ethyl] -4- ( 4-trifluoromethoxyphenyl) -1,2,3,6tetrahydropyridine (425 mg, 1.14 mmol) prepared in Reference Example 17, 2- [4 (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridin-1 - il] ethanol (222 mg, 68% yield) as a light brown oil was prepared in the same manner as described in Reference Example 14.

[0787] ¹ H NMR (CDCb) δ ppm:

[0788] 2.47 - 2.59 (2H, m), 2.68 (2H, t, J = 5.5 Hz), 2.79 (2H, t, J = 5.5 Hz), 3, 16 -

3.25 (2H, m), 3.70 (2H, t, J = 5.5 Hz), 6.00 - 6.10 (1H, m), 7.17 (2H, dd, J = 2, 1 Hz, 6.7

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390/854

Hz), 7.40 (2H, dd, J = 2.1 Hz, 6.7 Hz).

Reference Example 19

Preparation of 3- (4-trifluoromethylphenyl) -2-propin-1-ol [0789] A mixture of 4-bromobenzotrifluoride (6.5 g, 28.89 mmol), propargyl alcohol (2.35 ml, 40.45 mmol), triethylamine (5.64 ml, 40.45 mmol), triphenylphosphine (230 mg, 0.87 mmol), cuprous iodide (110 mg, 0.58 mmol), and dichlorobis (triphenylphosphine) palladium (210 mg, 0 , 29 mmol) in toluene (100 ml) was stirred at 100 ° C under a nitrogen atmosphere for 2 hours. The reaction mixture was allowed to return to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 3- (4-trifluoromethylphenyl) -2propin-1-ol (3.47 g, 60% yield) as a light brown oil.

[0790] ¹ H NMR (CDCb) δ ppm:

[0791] 4.52 (2H, d, J = 6.2 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz) .

Reference Example 20

Preparation of 2- [N-methyl- (4-trifluoromethoxyphenyl) amino] ethanol [0792] A mixture of N-methyl- (4-trifluoromethoxyphenyl) amine (4.83 g, 24.24 mmol), 2- (2- bromoethoxy) tetrahydropyran (6.1 g, 29.03 mmol), and potassium carbonate (3.84 g, 27.76 mmol) in DMF (20 ml) was stirred at 100 ° C for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving 2- [N-methyl- (4trifluoromethoxyphenyl) amino] ethanol (3.1 g, yield 53 %) as a light yellow oil.

[0793] ¹ H NMR (CDCb) δ ppm:

[0794] 2.96 (3H, s), 3.46 (2H, t, J = 5.7 Hz), 3.81 (2H, q, J = 5.7 Hz), 6.74 (2H, d,

J = 8.7 Hz), 7.08 (2H, d, J = 8.7 Hz).

Reference Example 21

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391/854

Preparation of 8- (4-trifluoromethoxyphenyl) -1,4-dioxa-8-azospiro [4,5] decane [0795] A mixture of 1-bromo-4- (trifluoromethoxy) benzene (6.3 g, 26.14 mmol), 1,4-dioxa-8-azospiro [4.5] decane (3.35 ml, 26.14 mmol), palladium acetate (60 mg, 0.26 mmol), (S) - (-) -2,2'-bis (diphenylphosphino) -1,1'-binaftyl (BINAP) (244 mg, 0.39 mmol), and sodium tert-butoxide (3.77 g, 39.23 mmol) in toluene ( 50 ml) was stirred at 80 ° C for 1 hour. The reaction mixture was allowed to return to room temperature, to which ethyl acetate (50 ml) was added, and the resulting mixture was then filtered. The filtrate was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving 8- (4-trifluoromethoxyphenyl) -1,4-dioxa-8-azospiro [4,5] decane ( 6.54 g, 83% yield) as a light yellow powder.

[0796] ¹ H NMR (CDCb) δ ppm:

[0797] 1.83 (4H, t, J = 5.8 Hz), 3.31 (4H, t, J = 5.8 Hz), 3.99 (4H, s), 6.90 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz).

Reference Example 22

Preparation of 1- (4-trifluoromethoxyphenyl) pipendin-4-one [0798] A mixture of 8- (4-trifluoromethoxyphenyl) -1,4-dioxa-8-azospiro [4,5] decane (1.23 g, 4 , 06 mmol) prepared in Reference Example 21, concentrated hydrochloric acid (5 ml), water (10 ml), and ethanol (30 ml) was heated to reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/1) giving 1- (4trifluoromethoxyphenyl) pipendin-4-one (848 mg, 81% yield) as an oil colorless.

[0799] ¹ H NMR (CDCb) δ ppm:

[0800] 2.56 (4H, t, J = 6.2 Hz), 3.59 (4H, t, J = 6.2 Hz), 6.94 (2H, d, J = 8.5 Hz) ,

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392/854

7.14 (2H, d, J = 8.5 Hz).

Reference Example 23

Preparation of 1- (4-trifluoromethoxyphenyl) pipendin-4-ol [0801] Sodium borohydride (324 mg, 8.56 mmol) was added to a solution of 1 - (4-trifluoromethoxyphenyl) piperidin-4-one (1 , 11 g, 4.28 mmol) prepared in Reference Example 22 in methanol (30 ml) while cooling in an ice bath, and the mixture was stirred for 30 minutes. 10% hydrochloric acid was added thereto, and the resulting mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/1) giving 1- (4-trifluoromethoxyphenyl) piperidin-4-ol (1.08 g, 97% yield ) as a white powder.

[0802] ¹ H NMR (CDCb) δ ppm:

[0803] 1.59 -1.76 (2H, m), 1.90 - 2.06 (2H, m), 2.82 - 2.98 (2H, m), 3.43 - 3.57 ( 2H,

m), 3.75 - 3.91 (1H, m), 6.89 (2H, d, J = 7.1 Hz), 7.09 (2H, d, J = 7.1 Hz).

[0804] Compounds of Reference Examples 24 and 25 were prepared in the same manner as described in Example 23.

Reference Example 24

- (4-trifluoromethylphenyl) piperidin-4-ol [0805] a white powder, 76% yield [0806] ¹ H NMR (CDCb) δ ppm:

[0807] 1.53-1.71 (2H, m), 1.89 - 2.04 (2H, m), 2.91 -3.11 (2H, m), 3.56 - 3.71 ( 2H,

m), 3.80 - 4.00 (1H, m), 6.93 (2H, d, J = 8.7 Hz), 7.46 (2H, d, J = 8.7 Hz).

Reference Example 25

- (4-methoxyphenyl) piperidin-4-ol [0808] a white powder, 5% yield [0809] ¹ H NMR (CDCb) δ ppm:

[0810] 1.64 -1.79 (2H, m), 1.92 - 2.08 (2H, m), 2.74 - 2.88 (2H, m), 3.32 - 3.47 ( 2H,

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m), 3.70 - 3.85 (4H, m), 6.84 (2H, dd, J = 2.4 Hz, 6.8 Hz), 6.93 (2H, dd, J = 2.4 Hz, 6.8 Hz).

Reference Example 26

Preparation of 1 - (4-chlorophenyl) piperidin-4-ol [0811] A mixture of 8- (4-chlorophenyl) -1,4-dioxa-8-azospiro [4,5] decane (2.6 g,

10.25 mmol), concentrated hydrochloric acid (12 ml), water (10 ml), and ethanol (50 ml) was heated to reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (50 ml), to which was added sodium borohydride (388 mg,

10.25 mmol) while cooling in an ice bath, and the mixture was stirred for 30 minutes. 10% hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/1) giving 1 - (4-chlorophenyl) piperidin-4-ol (1.73 g, 80% yield ) as a light yellow crystalline powder.

[0812] ¹ H NMR (CDCb) δ ppm:

[0813] 1.55 -1.74 (2H, m), 1.89 - 2.08 (2H, m), 2.79 - 3.00 (2H, m), 3.43 - 3.57 ( 2H,

m), 3.75 - 3.92 (1H, br), 6.89 (2H, d, J = 7.1 Hz), 7.09 (2H, d, J = 7.1 Hz).

[0814] Using a corresponding starting material, a compound of Reference Example 27 was prepared in the same manner as described in Reference Example 26.

Reference Example 27

- (4-fluorophenyl) piperid in-4-ol [0815] a white powder, 66% yield

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394/854 [0816] ¹ H NMR (CDCh) δ ppm:

[0817] 1.57-1.79 (2H, m), 1.92 - 2.08 (2H, m), 2.75 - 2.92 (2H, m), 3.36 - 3.50 ( 2H,

m), 3.74 - 3.89 (1H, m), 6.77 - 7.00 (4H, m).

Reference Example 28

Preparation of 4- [4- (tert-buti-dimethylisyloxy) piperidin-1-yl] benzonitrile [0818] A mixture of 4-bromobenzonitrile (2.76 g, 15.16 mmol), 4- (terbutyldimethylsiloxy) piperidine (2.9 g, 13.79 mmol), palladium acetate (62 mg, 0.28 mmol), (S) - (-) - 2,2'-bis (diphenylphosphino) -1, 1'-binaftyl (BINAP) (258 mg, 0.41 mmol), and sodium terbutoxide (1.99 g, 20.68 mmol) in toluene (60 ml) was stirred at 80 ° C for 1 hour. The reaction mixture was allowed to return to room temperature, to which ethyl acetate (60 ml) was added, and the mixture was filtered. The filtration was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / methylene chloride = 1/1) giving 4- [4- (terbutyldimethylsiloxy) piperidin-1-yl] benzonitrile (2.8 g, yield 66%) as a light yellow crystalline powder.

[0819] ¹ H NMR (CDCI3) δ ppm:

[0820] 0.90 (9H, s), 1.50 - 1.69 (8H, m), 1.73 - 1.90 (2H, m), 3.18-3.31 (2H, m) ,

3.50 - 3.65 (2H, m), 3.90 - 4.04 (1H, m), 6.85 (2H, d, J = 7.0 Hz), 7.47 (2H, d, J = 7.0 Hz).

Reference Example 29

Preparation of 4- (4-hydroxypiperidin-1-yl) benzonitrile [0821] Tetra-n-butylammonium fluoride solution (1M) THF (10.6 ml, 10.2 mmol) was added to a mixture of 4- [4- (tert-butyldimethylsiloxy) piperidin-1-yl] benzonitrile (2.8 g, 8.85 mmol) prepared in Reference Example 28 in THF (30 ml) while cooling in an ice bath, and the mixture it was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by means of

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395/854 column chromatography on silica gel (n-hexane / ethyl acetate = 1/2) giving 4- (4hydroxypiperidin-1-yl) benzonitrile (1.52 g, 85% yield) as a colorless crystalline powder .

[0822] ¹ H NMR (CDCb) δ ppm:

[0823] 1.50 -1.73 (2H, m), 1.90 - 2.04 (2H, m), 3.00 - 3.20 (2H, m), 3.59 - 3.76 ( 2H,

m), 3.84 - 4.04 (1H, m), 6.86 (2H, dd, J = 2.0 Hz, 7.1 Hz), 7.48 (2H, dd, J = 2.0 Hz, 7.1 Hz).

Reference Example 30

Preparation of ethyl 1- (4-trifluoromethylphenyl) piperidine-4-carboxylate [0824] Using 4-bromobenzotrifluoride (3.15 g, 13.99 mmol) and ethyl isonipecotate (2.2 g, 13.99 mmol), Ethyl 1- (4-trifluoromethylphenyl) piperidine-4-carboxylate (3.18 g, 74% yield) as a light brown crystalline powder was prepared in the same manner as described in Reference Example 21.

[0825] ¹ H NMR (CDCb) δ ppm:

[0826] 1.27 (3H, t, J = 7.2 Hz), 1.71 - 2.10 (4H, m), 2.41 - 2.55 (1H, m), 2.82 - 2 , 98 (2H, m), 3.65 - 3.80 (2H, m), 4.16 (2H, q, J = 7.2 Hz), 6.92 (2H, d, J = 6.9 Hz), 7.63 (2H, d, J = 6.9 Hz).

Reference Example 31

Preparation of [1- (4-trifluoromethylphenyl) pipehdin-4-yl] methanol [0827] Lithium aluminum hydride (1.58 g, 41.64 mmol) was suspended in THF (30 ml), to which was added a solution of ethyl 1- (4-trifluoromethylphenyl) pipehdino-4-carboxylate prepared in Reference Example 30 (3.18 g, 10.41 mmol) in THF (10 ml) by dripping while cooling in an ice bath under a nitrogen atmosphere. The mixture was stirred for 30 minutes. Water and 10% aqueous sodium hydroxide solution were added to the reaction mixture, which was filtered through Celite. The filtrate was extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving [1- (4-thfluoromethylphenyl) piperidin-4-yl] methanol (2.64 g, 98% yield) as a light yellow oil.

[0828] ¹ H NMR (CDCb) δ ppm:

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396/854 [0829] 1.31-1.47 (2H, m), 1.61-1.90 (3H, m), 2.74 - 2.90 (2H, m), 3.45 - 3 , 61 (2H,

m), 3.83 (2H, d, J = 12.6 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.8 Hz) . Reference Example 32

Preparation of 1- (4-trifluoromethoxybenzyl) pipendin-4-ol [0830] Sodium triacetoxyborohydride (1.67 g, 7.89 mmol) was added to a solution of 4- (trifluoromethoxy) benzaldehyde (1 g, 5, 26 mmol) and 4-hydroxy piperidine (798 mg, 7.89 mmol) in acetonitrile (2 ml) while cooling in an ice bath, and the mixture was stirred for 30 minutes, and then at room temperature for one hour. overnight. The reaction mixture was poured into a 7.5% aqueous sodium bicarbonate solution and extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) giving 1- (4trifluoromethoxybenzyl) piperidin-4-ol (1.21 g, 84% yield) as an oil light yellow.

[0831] ¹ H NMR (CDCb) δ ppm:

[0832] 1.50 -1.74 (2H, m), 1.80-1.98 (2H, m), 2.08 - 2.24 (2H, m), 2.63 - 2.84 ( 2H,

m), 3.49 (2H, s), 3.61 - 3.80 (1H, m), 7.15 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8.5 Hz). [0833] Compounds of Reference Examples 33 and 34 were prepared in the same manner as described in Reference Example 32.

Reference Example 33 1- (4-chlorobenzyl) piperidin-4-ol [0834] a white powder, 87% yield [0835] ¹ H NMR (CDCb) δ ppm:

[0836] 1.48 -1.63 (2H, m), 1.76 -1.91 (2H, m), 2.04 - 2.20 (2H, m), 2.61 - 2.76 ( 2H,

m), 3.45 (2H, s), 3.57 - 3.72 (1H, m), 7.24 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8 Hz). Reference Example 34

- (4-trifluoromethylIbenziI) piperidin-4-ol [0837] a white powder, 83% yield [0838] ¹ H NMR (CDCb) δ ppm:

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397/854 [0839] 1.43 -1.67 (2H, m), 1.80-1.94 (2H, m), 2.06 - 2.24 (2H, m), 2.63 - 2 , 78 (2H,

m), 3.67 (2H, s), 3.61 - 3.72 (1H, m), 7.44 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz). Reference Example 35

Preparation of ter-butyl (4-benzylpiperazin-1-yl) carbamate [0840] 4-Benzylpiperazin-1-yl-amine (36.03 g, 188 mmol) was dissolved in methanol (260 ml) and the solution was cooled in an ice bath, to which a solution of di-tert-butyl dicarbonate (61.66 g, 283 mmol) in methanol (100 ml) was added dripping over 20 minutes. The mixture was allowed to return to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / acetone = 3/1). Isopropyl ether (IPE) (60 ml) and nhexane (20 ml) were added to the solid thus obtained, and the mixture was stirred and then filtered giving primary crystals. The filtrate was concentrated under reduced pressure, isopropyl ether (10 ml) and n-hexane (10 ml) were added to the residue, and the mixture was stirred and then filtered giving secondary crystals. These crystals were combined and dried under reduced pressure giving tert-butyl (4-benzylpiperazin-1-yl) carbamate (42.22 g, 77% yield) as a colorless crystalline powder.

[0841] ¹ H NMR (CDCb) δ ppm:

[0842] 1.45 (9H, s), 2.55 - 2.58 (4H, m), 2.80 (4H, br), 3.51 (2H, s), 5.35 (1H, br ),

7.24-7.31 (5H, m).

Reference Example 36

Preparation of ter-butyl piperazin-1-yl-carbamate [0843] (4-benzylpiperazin-1-yl) ter-butyl carbamate (42.22 g, 145 mmol) prepared in Reference Example 35 was dissolved in ethanol ( 300 ml). To which 20% palladium hydroxide / carbon (6.0 g) was added, and the mixture was stirred at room temperature under atmospheric pressure of hydrogen for 20 minutes, and then at 50 ° C for 30 minutes. The catalyst was removed by means of filtration, and the filtrate was concentrated under reduced pressure. Solid thus obtained was washed with IPE, collected by filtration, and dried under reduced pressure giving tert-butyl piperazin-1-yl-carbamate (28.9 g, 99% yield) as a powder

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398/854 colorless crystalline.

[0844] ¹ H NMR (CDCb) δ ppm:

[0845] 1.46 (9H, s), 2.74 - 2.77 (4H, m), 2.95 - 2.99 (4H, m), 5.45 (1H, br).

Reference Example 37

Preparation of ter-butyl 4- (4-trifluoromethyl) piperidine-1-carboxylate [0846] ter-butyl 4-hydroxypiperidine-1-carboxylate (2.22 g, 10.0 mmol), 4-hydroxybenzotrifluoride (1.21 g, 7.45 mmol), tri-n-butylphosphine (2.26 g, 11.2 mmol) and 1, T (azodicarbonyl) dipiperidine (2.82 g, 11.2 mmol) were dissolved in benzene (20 ml ), and the mixture was stirred at room temperature for 2 days. Water was added to this, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (nhexane / ethyl acetate = 5/1) giving tert-butyl 4- (4-trifluoromethylphenoxy) pipendino-1-carboxylate (1.13 g, yield of 44%) as a colorless oil.

[0847] ¹ H NMR (CDCb) δ ppm:

[0848] 1.48 (9H, s), 1.65 - 1.82 (2H, m), 1.87 - 1.97 (2H, m), 3.34 - 3.44 (2H, m) ,

3.63 - 3.74 (2H, m), 4.47 - 4.58 (1H, m), 6.89 - 6.97 (2H, m), 7.47 - 7.55 (2H, m ). Reference Example 38

Preparation of 4- (4-trifluoromethylphenoxy) pipendin [0849] 4- (4-trifluoromethylphenoxy) pipendino-1-tert-butyl-1-carboxylate (1.13 g, 3.27 mmol) prepared in Reference Example 37 was dissolved in chloride methylene (10 ml). Trifluoroacetic acid (10 ml) was added thereto by dripping and the mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was again dissolved in methylene chloride. The solution was neutralized with an aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving 4- (4-trifluoromethylphenoxy) pipendin (727 mg, 91% yield) as a white powder.

[0850] ¹ H NMR (CDCb) δ ppm:

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399/854 [0851] 1.63 -1.75 (2H, m), 1.97 - 2.06 (2H, m), 2.69 - 2.80 (2H, m), 3.10 - 3 , 20 (2H,

m), 4.38 - 4.49 (1H, m), 6.94 - 6.98 (2H, m), 7.50 - 7.55 (2H, m).

[0852] Using corresponding starting materials, compounds of Reference Examples 39 to 43 were prepared in the same manner as described in Reference Example 38.

Reference Example 39

4- (4-fluorophenoxy) piperidine [0853] a white powder, 76% yield [0854] ¹ H NMR (CDCb) δ ppm:

[0855] 1.61 - 1.74 (2H, m), 1.96 - 2.06 (2H, m), 2.50 (1H, bs), 2.70 - 2.80 (2H, m) ,

3.11 - 3.20 (2H, m), 4.23 - 4.33 (1H, m), 6.80 - 6.89 (2H, m), 6.91 - 7.00 (2H, m ). Reference Example 40

4- (3-trifluoromethylphenoxy) pipendin [0856] a white powder, 48% yield [0857] ¹ H NMR (CDCb) δ ppm:

[0858] 1.62 - 1.76 (2H, m), 1.80 (1H, bs), 1.97 - 2.08 (2H, m), 2.71 - 2.81 (2H, m) ,

3.11 - 3.20 (2H, m), 4.37 - 4.47 (1H, m), 7.05 - 7.20 (3H, m), 7.34 - 7.41 (1H, m ). Reference Example 41

4- (4-trifluoromethoxyphenoxy) pipendin [0859] a white powder, 88% yield [0860] ¹ H NMR (CDCb) δ ppm:

[0861] 1.59-1.73 (3H, m), 1.97 -2.04 (2H, m), 2.68-2.78 (2H, m), 3.10 - 3.19 ( 2H,

m), 4.29 - 4.36 (1H, m), 6.85 - 6.92 (2H, m), 7.10 - 7.14 (2H, m).

Reference Example 42

4- (4-cyanophenoxy) piperidine [0862] a white powder, 83% yield [0863] ¹ H NMR (CDCb) δ ppm:

[0864] 1.63 -1.77 (3H, m), 1.98 - 2.08 (2H, m), 2.72-2.82 (2H, m), 3.12 - 3.21 ( 2H,

m), 4.42 - 4.51 (1H, m), 6.92 - 6.98 (2H, m), 7.55 - 7.61 (2H, m).

Reference Example 43

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4- (4-chlorophenoxy) piperidine [0865] a white powder, 62% yield [0866] ¹ H NMR (CDCb) δ ppm:

[0867] 1.50 (1H, bs), 1.56-1.71 (2H, m), 1.94 - 2.04 (2H, m), 2.66 - 2.76 (2H, m) ,

3.08 - 3.18 (2H, m), 4.25 - 4.35 (1H, m), 6.80 - 6.86 (2H, m), 7.18 - 7.25 (2H, m ). Reference Example 44

Preparation of 1-ethyl-5- (3-methyl-3-butenyl) -1 H-tetrazole [0868] N-butyl lithium solution (1.53 M) hexane (6.5 ml, 9 ml) was added dropwise , 98 mmol) to a solution of 1-ethyl-5-methyl-1 H-tetrazole (0.80 g, 7.13 mmol) in THF (15 ml) while stirring at -70 ° C, and the mixture was further stirred for 1.5 hours. A solution of 3-chloro-2-methyl-1-propene (0.77 ml, 7.84 mmol) in THF (5 ml) was added to the mixture, and the resulting mixture was stirred for 2 hours. Water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and then concentrated under reduced pressure to give 1-ethyl-5- (3-methyl-3 -butenyl) -1 H-tetrazole (0.95 g, 80% yield) as a brown oil.

[0869] ¹ H NMR (CDCb) δ ppm:

[0870] 1.56 (3H, t, J = 7.3 Hz), 1.80 (3H, s), 2.44 - 2.67 (2H, m), 2.90 - 3.06 (2H ,

m), 4.32 (2H, q, J = 7.3 Hz), 4.65 - 4.77 (1H, m), 4.77 - 4.87 (1H, m).

[0871] Using corresponding starting materials, compounds of Reference Examples 45 and 46 were prepared in the same manner as described in Reference Example 44.

Reference Example 45

-phen i-5- (3-methyl-3-butenyl) -1 H-tetrazole [0872] a white powder, 45% yield [0873] ¹ H NMR (CDCb) δ ppm:

[0874] 1.67 (3H, s), 2.49 (2H, t, J = 8.1 Hz), 3.04 (2H, t, J = 8.1 Hz), 4.58 - 4, 65 (1H, m), 4.71 - 4.77 (1H, m), 7.43 - 7.47 (2H, m), 7.59 - 7.62 (3H, m).

Reference Example 46

- (4-chlorophenyl) -5- (3-methyl-3-butenyl) -1 H-tetrazole

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401/854 [0875] a white powder, 55% yield [0876] ¹ H NMR (CDCb) δ ppm:

[0877] 1.68 (3H, s), 2.50 (2H, t, J = 8.1 Hz), 3.03 (2H, t, J = 8.1 Hz), 4.58 - 4, 63 (1H, m), 4.71 - 4.77 (1H, m), 7.38 - 7.44 (2H, m), 7.56 - 7.62 (2H, m).

Reference Example 47

Preparation of 3- (4-methyl-4-pentenyl) -3H-benzoxazol-2-one [0878] Potassium tert-butoxide (3.5 g, 31.2 mmol) was gradually added to a mixture of sodium bromide methyltriphenylphosphonium (11 g, 30.8 mmol) in THF (100 ml) while cooling in an ice bath, and the mixture was stirred for 20 minutes. To this was added by dripping a solution of 3- (4-oxopentyl) -3Hbenzoxazol-2-one (5.6 g, 25.6 mmol) in THF (10 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/1) giving 3- (4-methyl-4-pentenyl) -3Hbenzoxazol-2-one (3.4 g , 61% yield) as a colorless oil.

[0879] ¹ H NMR (CDCb) δ ppm:

[0880] 1.73 (3H, s), 1.84 - 2.16 (4H, m), 3.83 (2H, t, J = 7.3 Hz), 4.75 (2H, d, J =

12.7 Hz), 6.97 (1H, d, J = 8.2 Hz), 7.02 - 7.28 (3H, m).

Reference Example 48

Preparation of 3- (5-methyl-5-hexenyl) -3H-benzoxazol-2-one [0881] Using 3- (5-oxohexyl) -3H-benzoxazol-2-one (1.4 g, 6 mmol), 3- (5-methyl-5hexenyl) -3H-benzoxazol-2-one (1.1 g, 79% yield) as a colorless oil was prepared in the same manner as described in Reference Example 47.

[0882] ¹ H NMR (CDCb) δ ppm:

[0883] 1.42 - 1.60 (2H, m), 1.65 - 1.83 (5H, m), 2.00-2.16 (2H, m), 3.84 (2H, t, J = 6.9 Hz), 4.69 (2H, d, J = 11.7 Hz), 6.97 (1H, d, J = 7.9 Hz), 7.02 - 7.23 (3H, m). Reference Example 49

Preparation of 5- (4-trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazole-2-one

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402/854 [0884] Triethylamine (3.52 ml, 25.28 mmol) and 1, Τ-carbonyldiimidazole (4.84 g, 29.87 mmol) were added to a 4-trifluoromethoxybenzoic hydrazide solution (5.06 g , 22.98 mmol) in THF (150 ml) while cooling in an ice bath and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, to which water was added. The mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and then concentrated under reduced pressure to give 5- (4-trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazole-2-one ( 5.34 g, 94% yield) as a colorless crystalline powder. [0885] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0886] 7.01 (1H, s), 7.47 - 7.59 (2H, m), 7.86 - 7.98 (2H, m).

[0887] Using corresponding starting materials, compounds of Reference Examples 50 to 61 were prepared in the same manner as described in Reference Example 49.

Reference Example 50

5- (4-trifluoromethylphenyl) -3H- [1,3,4] oxadiazol-2-one [0888] a white powder, 97% yield [0889] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0890] 7.90 (2H, d, J = 8.5 Hz), 7.99 (2H, d, J = 8.5 Hz).

Reference Example 51

5- (4-biphenylyl) -3H- [1,3,4] oxadiazole-2-one [0891] a white powder, 97% yield [0892] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0893] 7.35 - 7.52 (3H, m), 7.68 - 7.73 (2H, m), 7.76 - 7.87 (4H, m).

Reference Example 52

5-phenyl-3H- [1,3,4] oxadiazole-2-one [0894] a white powder, 92% yield [0895] ¹ H NMR (CDCb) δ ppm:

[0896] 7.40 - 7.58 (3H, m), 7.77 - 7.91 (2H, m).

Reference Example 53

5- (4-chlorophenyl) -3H- [1,3,4] oxadiazole-2-one

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403/854 [0897] a white powder, 80% yield [0898] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0899] 7.61 (2H, dd, J = 1.9 Hz, 6.6 Hz), 7.80 (2H, dd, J = 1.9 Hz, 6.6 Hz).

Reference Example 54

5- (4-fluorophenyl) -3H- [1,3,4] oxadiazole-2-one [0900] a white powder, 74% yield [0901] ¹ H NMR (DMSO-de) δ ppm:

[0902] 7.30 - 7.49 (2H, m), 7.78 - 7.92 (2H, m).

Reference Example 55

5- (4-bromophenyl) -3H- [1,3,4] oxadiazole-2-one [0903] a white powder, 87% yield [0904] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0905] 7.65 - 7.78 (4H, m).

Reference Example 56

5- (4-chlorobenzyl) -3H- [1,3,4] oxadiazole-2-one [0906] a white powder, 83% yield [0907] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0908] 3.94 (2H, s), 7.31 (2H, dd, J = 2.1 Hz, 6.4 Hz), 7.41 (2H, dd, J = 2.1 Hz, 6, 4

Hz).

Reference Example 57

5- [2- (4-chlorophenyl) ethyl] -3H- [1,3,4] oxadiazol-2-one [0909] a white powder, 78% yield [0910] ¹ H NMR (DMSO-de) δ ppm:

[0911] 2.76 - 3.00 (4H, m), 7.27 (2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 12, 03 (1H, s).

Reference Example 58

5- (4-chlorostyryl) -3H- [1,3,4] oxadiazole-2-one [0912] a white powder, 88% yield [0913] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0914] 6.99 (1H, d, J = 16.5 Hz), 7.32 (1H, d, J = 16.5 Hz), 7.47 (2H, d, J = 8.6 Hz) ,

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7.75 (2H, d, J = 8.6 Hz), 12.06 (1H, s).

Reference Example 59

5- (4-chlorophenoxymethyl) -3H- [1,3,4] oxadiazol-2-one [0915] a white powder, 68% yield [0916] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0917] 5.07 (2H, s), 7.07 (2H, d, J = 6.8 Hz), 7.37 (2H, d, J = 6.8 Hz), 12.41 (1H, br).

Reference Example 60

5- (4-pyridyl) -3H- [1,3,4] oxadiazole-2-one [0918] a white powder, 40% yield [0919] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0920] 7.72 (2H, dd, J = 1.6 Hz, 4.6 Hz), 8.76 (2H, dd, J = 1.6 Hz, 4.6 Hz), 12.90 (1H ,s).

Reference Example 61

5- (2-pyrimidyl) -3H- [1,3,4] oxadiazole-2-one [0921] a white powder, 70% yield [0922] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[0923] 8.68-8.86 (2H, m), 9.12 (1H, d, J = 1.4 Hz), 12.97 (1H, s).

Reference Example 62

Preparation of ter-butyl (S) -2- (4-trifluoromethoxyphenoxymethyl) pyrrolidine-1-carboxylate [0924] A mixture of 4- (trifluoromethoxy) phenol (2.1 g, 11.8 mmol), (S) - Tert-butyl 2-hydroxymethyl pyrrolidine-1-carboxylate (2 g, 9.8 mmol), diethyl azodicarboxylate (2.3 ml, 14.7 mmol), and triphenylphosphine (3.86 g, 14.7 mmol) in THF (30 ml) was heated to reflux for 1 hour. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 10/1) giving (S) -2- (4-trifluoromethoxyphenoxymethyl) pyrrolidine-1-carboxylate (2) , 96 g, 65% yield) as a light yellow oil.

[0925] ¹ H NMR (CDCb) δ ppm:

[0926] 1.48 (9H, s), 1.78 - 2.10 (4H, m), 3.27 - 3.49 (2H, m), 3.73 - 3.98 (1H, m) ,

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4.04 - 4.20 (2H, m), 6.90 (2H, dd, J = 2.2 Hz, 7.0 Hz), 7.12 (2H, dd, J = 2.2 Hz, 7 , 0 Hz). Reference Example 63

Preparation of ter-butyl (S) -2- (4-trifluoromethoxyphenoxymethyl) pyrrolidine [0927] A mixture of ter-butyl (S) -2- (4-trifluoromethoxyphenoxymethyl) 1-carboxylate (2.31 g, 6.39 mmol ) prepared in Reference Example 62, trifluoroacetic acid (20 ml), and methylene chloride (20 ml) were stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with 10% aqueous sodium hydroxide solution and the mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving (S) 2- (4-trifluoromethoxyphenoxymethyl) pyrrolidine (1.65 g, 99% yield) as a light brown oil.

[0928] ¹ H NMR (CDCb) δ ppm:

[0929] 1.45 -1.63 (1H, m), 1.65 - 2.04 (3H, m), 2.70 (1H, bs), 2.88 - 3.08 (2H, m) ,

3.43 - 3.59 (1H, m), 3.78 - 3.96 (2H, m), 6.88 (2H, dd, J = 2.3 Hz, 8.4 Hz), 7.11 (2H, dd, J = 2.3 Hz, 8.4 Hz).

Reference Example 64

Preparation of ter-butyl 3-oxo-4- (4-trifluoromethylbenzyl) piperazine-1-carboxylate [0930] Sodium hydride (840 mg, 24.5 mmol) was gradually added to a solution of 3-oxopiperazine-1 tert-butyl carboxylate (4.1 g, 20.4 mmol) in DMF (30 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 30 minutes. A solution of 4-trifluoromethylbenzyl chloride (5 g, 20.9 mmol) in DMF (5 ml) was added dropwise to the mixture while cooling in an ice bath, which was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride) giving ter-butyl 3-oxo-4- (4-trifluoromethylbenzyl) piperazine-1-carboxylate (6.7 g, 91% yield ) as a colorless crystalline powder.

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406/854 [0931] ¹ H NMR (CDCb) δ ppm:

[0932] 1.47 (9H, s), 3.27 (2H, t, J = 5.7 Hz), 3.62 (2H, t, J = 5.7 Hz), 4.18 (2H, s),

4.67 (2H, s), 7.39 (2H, d, J = 8.1 Hz), 7.61 (2H, d, J = 8.1 Hz).

Reference Example 65

Preparation of 1- (4-trifluoromethylbenzyl) piperazine-2-one [0933] Using terbutyl 3-oxo-4- (4-trifluoromethylbenzyl) piperazine-1-carboxylate (6.7 g, 18.7 mmol) prepared in the Example Reference 64, 1- (4trifluoromethylbenzyl) piperazine-2-one (4.5 g, 93% yield) as a light yellow powder was prepared in the same manner as described in Reference Example 63. [0934] ¹ H NMR ( CDCb) δ ppm:

[0935] 3.06 (2H, t, J = 5.2 Hz), 3.24 (2H, t, J = 5.2 Hz), 3.62 (2H, s), 4.60 (2H, s),

7.39 (2H, d, J = 8.1 Hz), 7.59 (2H, d, J = 8.1 Hz).

Reference Example 66

Preparation of 4'-trifluoromethoxybiphenyl-4-carbaldehyde [0936] A mixture of 1-bromo-4- (trifluoromethoxy) benzene (1.53 g, 6.35 mmol), 4-formylbenzenoboronic acid (1 g, 6.67 mmol ), tetrakis (triphenylphosphino) palladium (147 mg, 0.13 mmol), and potassium phosphate (2.02 g, 9.53 mmol) in DMF (10 ml) was stirred at 100 ° C for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate, and the extract was washed with water three times and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (nhexane / methylene chloride = 3/1) giving 4'-trifluoromethoxybiphenyl-4-carbaldehyde (1.56 g, 92% yield) as a white powder.

[0937] ¹ H NMR (CDCb) δ ppm:

[0938] 7.33 (2H, d, J = 8.8 Hz), 7.60 - 7.80 (4H, m), 7.97 (2H, d, J = 8.2 Hz), 10, 07 (1H, s).

[0939] Compounds of Reference Examples 67 to 73 were prepared from the corresponding compounds of iodobenzene or bromobenzene and formylbenzenoboronic acids in the same manner as described in Reference Example 66.

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Reference Example 67

4'-trifluoromethylbiphenyl-4-carbaldehyde [0940] a colorless crystalline powder, 27% yield [0941] ¹ H NMR (CDCb) δ ppm:

[0942] 7.68 - 7.81 (6H, m), 7.99 (2H, dd, J = 1.7 Hz, 6.5 Hz), 10.09 (1H, s).

Reference Example 68

4'-trifluoromethylbiphenyl-3-carbaldehyde [0943] a yellow oil, 83% yield [0944] ¹ H NMR (CDCb) δ ppm:

[0945] 7.33 (2H, d, J = 8.8 Hz), 7.60 - 7.80 (4H, m), 7.97 (2H, d, J = 8.2 Hz), 10, 07 (1H, s).

Reference Example 69

4'-dimethylaminobiphenyl-4-carbaldehyde [0946] a yellow powder, 46% yield [0947] ¹ H NMR (CDCb) δ ppm:

[0948] 3.03 (6H, s), 6.81 (2H, dd, J = 2.1 Hz, 6.8 Hz), 7.58 (2H, dd, J = 2.1 Hz, 6, 8

Hz), 7.71 (2H, dd, J = 1.8 Hz, 6.6 Hz), 7.90 (2H, dd, J = 1.8 Hz, 6.6 Hz), 10.00 (1H , s). Reference Example 70

4'-chlorobiphenyl-4-carbaldehyde [0949] a light yellow crystalline powder, 47% yield [0950] ¹ H NMR (CDCb) δ ppm:

[0951] 7.45 (2H, d, J = 8.6 Hz), 7.57 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.4 Hz) ,

7.96 (2H, d, J = 8.4 Hz), 10.06 (1H, s).

Reference Example 71

2'-chlorobiphenyl-4-carbaldehyde [0952] a colorless crystalline powder, 46% yield [0953] ¹ H NMR (CDCb) δ ppm:

[0954] 7.30 - 7.40 (3H, m), 7.38 - 7.58 (1H, m), 7.63 (2H, d, J = 8.1 Hz), 7.96 (2H , d, J = 8.1 Hz), 10.08 (1H, s).

Reference Example 72

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3 ', 4'-dichlorobiphenyl-4-carbaldehyde [0955] a colorless crystalline powder, 24% yield [0956] ¹ H NMR (CDCb) δ ppm:

[0957] 7.46 (1H, dd, J = 2.1 Hz, 8.4 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.70 - 7.80 (3H,

m), 7.97 (2H, dd, J = 1.8 Hz, 6.6 Hz), 10.07 (1H, s).

Reference Example 73 4'-methoxybiphenyl-4-carbaldehyde [0958] a colorless crystalline powder, 45% yield [0959] ¹ H NMR (CDCb) δ ppm:

[0960] 3.87 (3H, s), 7.01 (2H, d, J = 6.8 Hz), 7.59 (2H, d, J = 6.8 Hz), 7.72 (2H, d,

J = 8.3 Hz), 7.93 (2H, d, J = 8.3 Hz), 10.04 (1H, s).

Reference Example 74

Preparation of 4- (pyridin-3-yl) benzaldehyde [0961] A mixture of 4-bromobenzaldehyde (2 g, 10.8 mmol), diethyl (3 pyridyl) borane (1.75 g, 11.9 mmol), tetrakis ( triphenylphosphine) palladium (375 mg, 0.32 mmol), and 2N aqueous sodium carbonate solution (10.8 ml, 21.6 mmol) in toluene (40 ml) was heated to reflux under a one-day nitrogen atmosphere To the other. The reaction mixture was allowed to return to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving 4- (pyridin-3-yl) benzaldehyde (1.43 g, 72% yield) as a light yellow crystalline powder.

[0962] ¹ H NMR (CDCb) δ ppm:

[0963] 7.33 - 7.50 (1H, m), 7.76 (2H, dd, J = 1.8 Hz, 6.6 Hz), 7.89 - 8.06 (3H, m),

8.56-8.69 (1H, m), 8.90 (1H, dd, J = 0.7 Hz, 1.7 Hz), 10.09 (1H, s).

Reference Example 75

Preparation of 4- (imidazol-1-yl) benzaldehyde [0964] A mixture of 4-fluorobenzaldehyde (4.96 g, 40 mmol), imidazole (2.86 g, 42 mmol), and potassium carbonate (6.08 g, 44 mmol) in DMSO (40 ml) was stirred at

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110 ° C overnight. The reaction mixture was allowed to return to room temperature, and poured into ice water (100 ml). The resulting precipitates were collected by filtration and washed with water and then with ethyl acetate giving 4- (imidazol-1-yl) benzaldehyde (2.33 g, 34% yield) as a light yellow crystalline powder.

[0965] ¹ H NMR (CDCb) δ ppm:

[0966] 7.20 - 7.30 (1H, m), 7.38 (1H, dd, J = 1.3 Hz, 1.4 Hz), 7.58 (2H, dd, J = 1.8

Hz, 6.8 Hz), 7.98 - 8.10 (3H, m), 10.05 (1H, s).

[0967] Using a corresponding starting material, a compound of Reference Example 76 was prepared in the same manner as described in Reference Example 75.

Reference Example 76

4- (piperid in-1-yl) benzaldehyde [0968] a yellow crystalline powder, 46% yield [0969] ¹ H NMR (CDCb) δ ppm:

[0970] 1.58 - 1.75 (6H, m), 3.33 - 3.50 (4H, m), 6.89 (2H, dd, J = 1.9 Hz, 7.0 Hz),

7.73 (2H, dd, J = 1.9 Hz, 7.0 Hz), 9.75 (1H, s).

Reference Example 77

Preparation of tert-butyl 4- (4-trifluoromethylphenyl) piperazine-1-carboxylate [0971] A mixture of 4-bromobenzotrifluoride (3.0 g, 13.3 mmol), ter-butyl piperazine-1-carboxylate (2.9 g, 15.3 mmol), bis (dibenzylidenoacetone) palladium (306 mg, 0.53 mmol), tri-o-tolylphosphine (162 mg, 0.53 mmol), and sodium ter-butoxide (2.2 g, 22.7 mmol) in toluene (60 ml) was refluxed under an atmosphere of nitrogen for 4 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred a little, and the insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / methylene chloride = 2/1) giving 4 (4-trifluoromethylphenyl) piperazine-1-carboxylate -butyl (3.8 g, 87% yield)

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410/854 as a white powder.

[0972] ¹ H NMR (CDCb) δ ppm:

[0973] 1.49 (9H, s), 3.21 - 3.26 (4H, m), 3.56 - 3.61 (4H, m), 6.90 - 6.93 (2H, m) ,

7.47-7.51 (2H, m).

[0974] Using corresponding starting materials, compounds of Reference Examples 78 to 84 were prepared in the same manner as described in Reference Example 77.

Reference Example 78

Terbutyl 4- (4-trifluoromethoxyphenyl) piperazine-1-carboxylate [0975] a white powder, 95% yield [0976] ¹ H NMR (CDCb) δ ppm:

[0977] 1.48 (9H, s), 3.09 - 3.13 (4H, m), 3.55 - 3.60 (4H, m), 6.87 - 6.91 (2H, m) ,

7.10-7.14 (2H, m).

Reference Example 79

Ter-butyl 4- (4-biphenylyl) piperazine-1-carboxylate [0978] a white powder, 95% yield [0979] ¹ H NMR (CDCb) δ ppm:

[0980] 1.49 (9H, s), 3.16 - 3.21 (4H, m), 3.58 - 3.62 (4H, m), 6.97 - 7.01 (2H, m) ,

7.27 - 7.32 (1H, m), 7.37 - 7.44 (2H, m), 7.50 - 7.58 (4H, m).

Reference Example 80

Ter-butyl 4- (4-dimethylaminophenyl) piperazine-1-carboxylate [0981] a white powder, 79% yield [0982] ¹ H NMR (CDCb) δ ppm:

[0983] 1.48 (9H, s), 2.87 (6H, s), 2.96 - 3.00 (4H, m), 3.54 - 3.59 (4H, m), 6.72 6.77 (2H, m), 6.87-6.92 (2H, m).

Reference Example 81

Tert-butyl 4- (3-pyridyl) piperazine-1-carboxylate [0984] a white powder, 99% yield [0985] ¹ H NMR (CDCb) δ ppm:

[0986] 1.49 (9H, s), 3.14 - 3.19 (4H, m), 3.57 - 3.62 (4H, m), 7.17 - 7.19 (2H, m) ,

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8.12 - 8.14 (1H, m), 8.31 - 8.33 (1 Η, m).

Reference Example 82

Ter-butyl 4- (4-ethoxycarbonylphenyl) piperazine-1-carboxylate [0987] a white powder, 42% yield [0988] ¹ H NMR (CDCb) δ ppm:

[0989] 1.37 (3H, t, J = 7.1 Hz), 1.48 (9H, s), 3.27 - 3.32 (4H, m), 3.56 - 3.60 (4H ,

m), 4.33 (2H, q, J = 7.1 Hz), 6.84 - 6.88 (2H, m), 7.92 - 7.96 (2H, m).

Reference Example 83 ter-butyl 4- (4-methylphenyl) piperazine-1-carboxylate [0990] a white powder, 55% yield [0991] ¹ H NMR (CDCb) δ ppm:

[0992] 1.48 (9H, s), 2.27 (3H, s), 3.04 - 3.09 (4H, m), 3.55 - 3.59 (4H, m), 6.82 6.87 (2H, m), 7.06 - 7.10 (2H, m).

Reference Example 84

Tert-butyl 4- (4-cyanophenyl) piperazine-1-carboxylate [0993] a white powder, 86% yield [0994] ¹ H NMR (CDCb) δ ppm:

[0995] 1.49 (9H, s), 3.28 - 3.33 (4H, m), 3.56 - 3.60 (4H, m), 6.83 - 6.87 (2H, m) ,

7.49-7.53 (2H, m).

Reference Example 85

Preparation of tert-butyl 1- (4-trifluoromethylphenyl) piperazine [0996] 4- (4-trifluoromethylphenyl) piperazine-1-carboxylate (3.8 g, 11.5 mmol) prepared in Reference Example 77 was dissolved in chloride methylene (40 ml), to which trifluoroacetic acid (10 ml) was added by dripping, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving 1- (4-trifluoromethylphenyl) piperazine (2.5 g, 96% yield) as a white powder.

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412/854 [0997] ¹ H NMR (CDCb) δ ppm:

[0998] 3.01 - 3.06 (4H, m), 3.21 - 3.26 (4H, m), 6.92 (2H, d, J = 8.6 Hz), 7.48 (2H , d, J = 8.6 Hz).

[0999] Using corresponding starting materials, compounds of Reference Examples 86 to 89 were prepared in the same manner as described in Reference Example 85.

Reference Example 86

1- (4-trifluoromethoxyphenyl) piperazine [1000] a white powder, 100% yield [1001] ¹ H NMR (CDCb) δ ppm:

[1002] 1.61 (1H, s), 3.00 - 3.05 (4H, m), 3.10 - 3.15 (4H, m), 6.85 - 6.92 (2H, m) ,

7.08-7.13 (2H, m).

Reference Example 87

1- (4-dimethylaminophenyl) piperazine [1003] a white powder, 99% yield [1004] ¹ H NMR (CDCb) δ ppm:

[1005] 1.60 (1H, br), 2.86 (6H, s), 3.01 (8H, br), 6.71 - 6.78 (2H, m), 6.87 - 6.92 (2H, m).

Reference Example 88

- (3-pyridyl) piperazine [1006] a white powder, 100% yield [1007] ¹ H NMR (CDCb) δ ppm:

[1008] 2.09 (1H, s), 3.03 - 3.09 (4H, m), 3.14 - 3.20 (4H, m), 7.16 - 7.18 (2H, m) ,

8.09- 8.11 (1H, m), 8.31 (1H, s).

Reference Example 89

1- (4-ethoxycarbonylphenyl) piperazine [1009] a white powder, 95% yield [1010] ¹ H NMR (CDCb) δ ppm:

[1011] 1.37 (3H, t, J = 7.1 Hz), 1.84 (1H, s), 3.00-3.04, (4H, m), 3.26-3.31 ( 4H,

m), 4.33 (2H, q, J = 7.1 Hz), 6.83 - 6.89 (2H, m), 7.89 - 7.96 (2H, m).

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Reference Example 90

Preparation of tert-butyl 4- (piperazin-1-yl) benzoate [1012] A mixture of tert-butyl 4-bromobenzoate (4.8 g, 18.8 mmol), piperazine (9.7 g, 0, 11 mol), palladium acetate (85 mg, 0.38 mmol), (S) - (-) - BINAP (352 mg, 0.57 mmol), and sodium ter-butoxide (2.7 g, 28, 2 mmol) in toluene (50 ml) was refluxed under a nitrogen atmosphere for 2 hours. Ethyl acetate and water were added to the reaction mixture and the insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 5/1) giving tert-butyl 4 (piperazin-1-yl) benzoate (3 , 8 g, 77% yield) as a gray powder. [1013] ¹ H NMR (CDCb) δ ppm:

[1014] 1.57 (9H, s), 3.00 - 3.04 (4H, m), 3.24 - 3.29 (4H, m), 6.83 - 6.87 (2H, m) ,

7.85-7.89 (2H, m).

Reference Example 91

Preparation of benzyl 4-trifluoromethoxypiperazine-1-carboxylate [1015] To a solution of 4-trifluoromethoxybenzyl alcohol (25 g, 130.11 mmol) and phenyl chloroformate (20.37 g, 130.11 mmol) in acetate ethyl (125 ml), a solution of pyridine (11.6 ml, 143.12 mmol) in ethyl acetate (50 ml) below 15 ° C was added dropwise over 35 minutes. The mixture was stirred for 30 minutes. The reaction mixture was washed with water, 3 N hydrochloric acid, 10% aqueous potassium carbonate solution and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving a carbonate compound as a colorless oil. To a solution of piperazine (33.62 g, 390.34 mmol) in methanol (125 ml), a solution of the carbonate compound in ethyl acetate (50 ml) was added dropwise below 10 ° C over 25 minutes. The resulting mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) giving 4-trifluoromethoxypiperazine-1-carboxylate

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414/854 benzyl (35.33 g, 89% yield) as a colorless oil.

[1016] ¹ H NMR (CDCb) δ ppm:

[1017] 2.57 - 2.96 (4H, m), 3.42 - 3.63 (4H, m), 5.13 (2H, s), 7.21 (2H, d, J = 8, 5

Hz), 7.39 (2H, d, J = 8.5 Hz).

Reference Example 92

Preparation of 3- (4-trifluoromethylphenyl) -2-propenyl piperazine-1-carboxylate [1018] A solution of pyridine (0.5 ml, 6.18 mmol) in ethyl acetate (2 ml) was added gradually by dripping to a solution of 3- (4-trifluoromethylphenyl) 2-propen-1-ol (1 g, 4.95 mmol) and phenyl chloroformate (0.72 ml, 5.69 mmol) in ethyl acetate (5 ml) while cooled in an ice bath. The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water, 3 N hydrochloric acid, 10% aqueous potassium carbonate solution and brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving a carbonate compound as a colorless oil. To a solution of piperazine (1.28 g, 14.84 mmol) in methanol (5 ml), a solution of the carbonate compound in ethyl acetate (5 ml) was added by dripping while cooling in an ice bath . The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) giving 3- (4trifluoromethylphenyl) piperazine-1-carboxylate -2 -propenyl (1.4 g, 90% yield) as a colorless oil. [1019] ¹ H NMR (CDCb) δ ppm:

[1020] 2.75 - 2.95 (4H, m), 3.43 - 3.57 (4H, m), 4.78 (2H, dd, J = 1.2 Hz, 6.0 Hz),

6.33 - 6.43 (1H, m), 6.66 (1H, d, 16.0 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.57 (2H, d , J = 8.4 Hz).

[1021] Using a corresponding starting material, a compound of Reference Example 93 was prepared in the same manner as described in Reference Example 92.

Reference Example 93

3- (4-Trifluoromethoxyphenyl) -2-propenyl piperazine-1-carboxylate

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415/854 [1022] a colorless oil, 90% yield [1023] ¹ H NMR (CDCb) δ ppm:

[1024] 2.75 - 2.88 (4H, m), 3.44 - 3.52 (4H, m), 4.75 (2H, dd, J = 1.3 Hz, 6.2 Hz),

6.29 (1H, dt, J = 6.2 Hz, 15.9 Hz), 6.62 (1H, d, J = 15.9 Hz), 7.15-7.18 (2H, m), 7.38 -7.42 (2H, m).

Reference Example 94

Preparation from 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine-1-carbonyl chloride [1025] A mixture of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (1 g, 4.3 mmol), pyridine (680 mg, 8.6 mmol), and triphosgene (430 mg, 1.45 mmol) in toluene (20 ml) was heated to reflux for 3 hours. The reaction mixture was allowed to return to room temperature and diluted with diethyl ether. The mixture was washed with 10% hydrochloric acid, water and brine in that order, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine-1-carbonyl chloride (1 g, 90% yield) as a yellow oil.

[1026] ¹ H NMR (CDCb) δ ppm:

[1027] 2.51 - 2.72 (2H, m), 3.81 - 4.00 (2H, m), 4.26 - 4.40 (2H, m), 5.93 - 6.09 ( 1H,

m), 7.16-7.35 (4H, m).

Reference Example 95

Preparation of 1-benzyl-4- (4-trifluoromethylphenyl) piperidin-4-ol [1028] 4-Bromobenzotrifluoride (1 g, 4.44 mmol) was dissolved in THF (15 ml), to which was added dripping solution of n-butyl lithium (1.5 M) hexane (3.1 ml, 4.67 mmol) at -70 ° C. Then, a solution of 1-benzyl4-piperidone in THF (15 ml) was added dropwise to the mixture, and the resulting mixture was stirred for 2 hours and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / acetone = 2/1) giving 1-benzyl-4- (4-trifluoromethylphenyl) piperidin-4-ol (692 mg, 46% yield ) as a colorless crystalline powder.

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416/854 [1029] ¹ H NMR (CDCb) δ ppm:

[1030] 1.60 -1.78 (2H, m), 2.07 - 2.25 (2H, m), 2.38 - 2.54 (2H, m), 2.74 - 2.87 ( 2H,

m), 3.59 (2H, s), 7.20 - 7.38 (5H, m), 7.51 - 7.67 (4H, m).

Reference Example 96

Preparation of 1-benzyl-4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine [1031] A mixture of 1-benzyl-4- (4-trifluoromethylphenyl) piperidin-4-ol (692 mg, 2 , 06 mmol) prepared in Reference Example 95, concentrated hydrochloric acid (4.5 ml) and acetic acid (10 ml) was heated to reflux overnight. The reaction mixture was allowed to return to room temperature, and diluted with methylene chloride. The mixture was washed with water, 10% aqueous sodium hydroxide solution and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / acetone = 4/1) giving 1-benzyl-4- (4-trifluoromethylphenyl) -1,2,3,6tetrahydropyridine (528 mg, yield 80%) as a light yellow crystalline powder.

[1032] ¹ H NMR (CDCb) δ ppm:

[1033] 2.50 - 2.60 (2H, m), 2.62 - 2.76 (2H, m), 3.11 - 3.22 (2H, m), 3.65 (2H, s) ,

6.10-6.20 (1H, m), 7.20-7.54 (9H, m).

Reference Example 97

Preparation of 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine [1034] 1-Benzyl-4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (2 g, 6 , 3 mmol) prepared in Reference Example 96 was dissolved in methylene chloride (20 ml), to which was added by dropping ethyl 2-chlorochloroformate (1.67 g, 11.68 mmol) under a nitrogen atmosphere while cooled in an ice bath, and the mixture was stirred at the same temperature for 3 hours. Methanol (20 ml) was added to the mixture, which was heated to reflux for 1 hour. The reaction mixture was allowed to return to room temperature, to which diethyl ether was added, and the resulting precipitates were collected by filtration giving 4 (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (1 , 44 g, 87% yield) as a colorless crystalline powder.

[1035] ¹ H NMR (DMSO-d ₆ ) δ ppm:

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417/854 [1036] 2.64-2.80 (2H, m), 3.18 - 3.34 (2H, m), 3.68 - 3.80 (2H, m), 6.25 - 6 , 39 (1H,

m), 7.61 -7.80 (4H, m).

Reference Example 98

Preparation of 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1carbonyl hydrochloride [1037] Using 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (300 mg, 1.14 mmol) prepared in Reference Example 97, pyridine (0.18 ml, 2.28 mmol) and triphosgene (112 mg, 0.38 mmol), 4- (4-trifluoromethylphenyl) -1,2 hydrochloride, 3,6tetrahydropyridine-1-carbonyl (220 mg, 67% yield) as a yellow oil was prepared in the same manner as described in Reference Example 94.

[1038] ¹ H NMR (CDCb) δ ppm:

[1039] 2.57-2.75 (2H, m), 3.82 -4.00 (2H, m), 4.25-4.40 (2H, m), 6.05 -6.16 ( 1H,

m), 7.47 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz).

Reference Example 99

Preparation of 4- (4-chlorophenyl) piperidine hydrochloride [1040] A mixture of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (2 g, 8.7 mmol) and platinum oxide (100 mg) in ethanol (100 ml) was stirred at room temperature under atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting precipitates by treatment of the residue with diethyl ether were collected by filtration giving 4- (4-chlorophenyl) piperidine hydrochloride (1.9 g, 94% yield) as a light gray powder.

[1041] ¹ H NMR (DMSO-Ó6) δ ppm:

[1042] 1.75 - 1.95 (4H, m), 2.74 - 3.05 (3H, m), 3.25 - 3.44 (2H, m), 7.25 (2H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.5 Hz).

Reference Example 100

Preparation of 4- (4-trifluoromethylphenyl) piperidine [1043] A mixture of 1-benzyl-4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (528 mg, 1.66 mmol) prepared in the Example Reference 96 and 10% palladium / carbon (50 mg) in acetic acid (5 ml) was stirred at room temperature

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418/854 under atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride, and the mixture was washed with water, 10% aqueous sodium hydroxide solution and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 4- (4-trifluoromethylphenyl) piperidine (400 mg, quantitative) as a yellow oil.

[1044] ¹ H NMR (CDCb) δ ppm:

[1045] 1.72 - 2.00 (4H, m), 2.61 - 2.84 (3H, m), 3.07 - 3.27 (2H, m), 7.32 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

Reference Example 101

Preparation of 4- (4-trifluoromethylphenyl) pipendin-1-carbonyl hydrochloride [1046] Using 4- (4-trifluoromethylphenyl) pipendin (760 mg, 3.32 mmol) prepared in Reference Example 100, 4- (4 -trifluoromethylphenyl) pipendino-1 carbonyl (crude product) a light brown oil was prepared in the same manner as described in Reference Example 94.

[1047] ¹ H NMR (CDCb) δ ppm:

[1048] 1.65 -1.84 (2H, m), 1.86 - 2.02 (2H, m), 2.77 - 3.28 (3H, m), 4.42 - 4.60 ( 2H,

m), 7.32 (2H, d, J = 8.1 Hz), 7.59 (2H, d, J = 8.1 Hz).

Reference Example 102

Preparation of 2- [3- (4-trifluoromethylphenyl) -2-propenyl] phthalim [1049] 4- (Trifluoromethyl) cinnamyl alcohol (3 g, 14.84 mmol) was dissolved in THF (60 ml), and added Phthalimide (2.84 g, 19.29 mmol) and triphenylphosphine (5.84 g, 22.26 mmol) were added to the solution, to which a solution of diethyl azodicarboxylate (3.87 g, 22 g) was gradually added by dripping. , 26 mmol) in THF (20 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / methylene chloride = 1/1) giving 2- [3- (4-trifluoromethylphenyl) - 2propenyl] phthalimide (4.57 g, 93% yield) as a white powder.

[1050] ¹ H NMR (CDCb) δ ppm:

[1051] 4.47 (2H, dd, J = 1.2 Hz, 6.3 Hz), 6.27-6.41 (1H, m), 6.68 (1H, d, J = 15.9

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419/854

Hz), 7.44 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.74 (2H, dd, J = 2.0 Hz, 7.0 Hz), 7.85 (2H, dd, J = 2.0 Hz, 7.0 Hz).

Reference Example 103

Preparation of 3- (4-trifluoromethylphenyl) -2-propenylamine [1052] A mixture of 2- [3- (4-trifluoromethylphenyl) -2-propenyl] phthalimide (4.57 g, 13.79 mmol) prepared in the Example Reference 102 and hydrazine hydrate (897 mg, 17.93 mmol) in ethanol (80 ml) were heated to reflux for 3 hours. The reaction mixture was allowed to return to room temperature and filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting mixture was washed with 1N aqueous sodium hydroxide solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 3- (4-trifluoromethylphenyl) -2-propenylamine (2.78 g, quantitative) as a light brown crystalline powder.

[1053] ¹ H NMR (CDCb) δ ppm:

[1054] 3.51 (2H, d, J = 4.7 Hz), 6.31 - 6.47 (1H, m), 6.55 (1H, d, J = 16.0 Hz), 7, 45 (2H, d, J = 8.3 Hz), 7.55 (2H, d, J = 8.3 Hz).

Reference Example 104

Preparation of piperazin-1-yl- (5-chlorobenzofuran-2-yl methylene) amine [1055] 1-Aminopiperazine (29 g, 287 mmol) was dissolved in isopropyl alcohol (173 ml), to which 5-chlorobenzofuran was added -2-aldehyde (34.52 g, 191 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel giving piperazin-1-yl- (5-chlorobenzofuran-2-yl methylene) amine (49.49 g, yield 98%) as a yellow crystalline powder. [1056] ¹ H NMR (CDCb) δ ppm:

[1057] 2.95-3.10 (4H, m), 3.17 - 3.29 (4H, m), 6.70 (1H, s), 7.20 (1H, dd, J = 2, 1

Hz, 8.7 Hz), 7.38-7.52 (3H, m).

Reference Example 105

Preparation of piperazin-1-yl- (4-trifluoromethyl benzylidene) amine [1058] Piperazin-1-yl-carbamate tert-butyl (403 mg, 2.0 mmol) was suspended in

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420/854 methylene chloride (4 ml), to which trifluoroacetic acid (1.6 ml) was added, and the mixture was stirred at room temperature for 5 minutes. To this was added 4 (trifluoromethyl) benzaldehyde (0.3 ml, 2.2 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 9/1) giving piperazin-1-yl- (4trifluoromethylbenzylidene) amine (432 mg, 84% yield) as a colorless crystalline powder .

[1059] ¹ H NMR (CDCb) δ ppm:

[1060] 3.00 - 3.29 (8H, m), 7.43 - 7.62 (3H, m), 7.68 (2H, d, J = 8.2 Hz).

Reference Example 106

Preparation of piperazin-1-yl- (4-trifluoromethoxy benzylidene) amine [1061] To a solution of 4-benzylpiperazin-1-yl-amine (43.18 g, 225 mmol) in ethanol (400 ml), was added a 20% suspension of palladium / carbon hydroxide (6.50 g) in ethanol (30 ml), and the mixture was stirred at room temperature under atmospheric pressure of hydrogen for 3 hours and then at 50 ° C for 2 hours. The reaction mixture was filtered through Celite, 4- (trifluoromethoxy) benzaldehyde (42.92 g, 225 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) giving piperazin-1-yl- (4trifluoromethoxybenzylidene) amine (56, 88 g, 93% yield) as a light yellow crystalline powder.

[1062] ¹ H NMR (CDCb) δ ppm:

[1063] 3.00 - 3.23 (8H, m), 7.18 (2H, d, J = 8.7 Hz), 7.58 (1H, s), 7.62 (2H, d, J =

8.7 Hz).

[1064] Using a corresponding starting material, a compound of Reference Example 107 was prepared in the same manner as described in

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421/854

Reference Example 106.

Reference Example 107

Piperazin-1-yl- (5-trifluoromethylbenzofuran-2-yl methylene) amine [1065] a light yellow crystalline powder, 77% yield [1066] ¹ H NMR (CDCb) δ ppm:

[1067] 3.00 - 3.14 (4H, m), 3.23 - 3.32 (4H, m), 6.79 (1H, s), 7.41 - 7.59 (3H, m) ,

7.82 (1H, s).

Reference Example 108

Preparation of (4-benzylpiperazin-1-yl) - (4-trifluoromethylphenyl) amine [1068] A mixture of 4-bromobenzotrifluoride (3.00 g, 13.3 mmol), 4-benzylpiperazin-1-yl-amine (3.06 g, 16.0 mmol), palladium acetate (60 mg, 0.267 mmol), (S) - (-) - BINAP (174 mg, 0.280 mmol) and sodium ter-butoxide (1.92 g, 20.0 mmol) in toluene (60 ml) was refluxed under an atmosphere of nitrogen for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was then purified by column chromatography on silica gel (n-hexane / acetone = 4/1) giving (4-benzylpiperazin-1-yl) - (4-trifluoromethylphenyl) ) amine (2.666 g, 59% yield) as a light yellow oil.

[1069] ¹ H NMR (CDCb) δ ppm:

[1070] 2.58 (4H, br), 2.76 (4H, br), 3.55 (2H, s), 4.65 (1H, br), 6.90 (2H, d, J = 8 , 6

Hz), 7.23 - 7.35 (5H, m), 7.41 (2H, d, J = 8.6 Hz).

Reference Example 109

Preparation of piperazin-1-yl- (4-trifluoromethylphenyl) amine [1071] A mixture of (4-benzylpiperazin-1-yl) - (4-trifluoromethylphenyl) amine prepared in Reference Example 108 and 10% palladium / carbon ( 0.53 g) in ethanol (50 ml) was stirred at room temperature under atmospheric pressure of hydrogen for 6 hours, and then at 60 ° C for 10 hours. After the catalyst was removed by filtration through Celite, 10% palladium / carbon (0.53 g) was added to the filtrate, and the mixture was stirred at 60 ° C under a pressure

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422/854 atmospheric hydrogen for 8 hours. After the catalyst was removed by filtration through Celite, the filtrate was concentrated under reduced pressure. The resulting solid was dried in vacuo giving piperazin-1-yl- (4-trifluoromethylphenyl) amine (1.76 g, 90% yield) as a colorless crystalline powder.

[1072] ¹ H NMR (CDCb) δ ppm:

[1073] 2.71 (4H, br), 3.00 (4H, t, J = 4.8 Hz), 4.71 (1H, br), 6.92 (2H, d, J = 8.5 Hz),

7.42 (2H, d, J = 8.5 Hz).

Reference Example 110

Preparation of ter-butyl 4- (3-phenyl-2-propenyloxy) piperidine-1-carboxylate [1074] 4-hydroxypiperidine-1-carboxylate (0.396 g, 1.97 mmol) was dissolved in DMF ( 5 ml), to which sodium hydride (0.086 g, 2.16 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Cinamyl chloride (0.300 g, 1.97 mmol) was added to the mixture while cooling in an ice bath, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (n-hexane / ethyl acetate = 6/1) yielding ter-butyl 4- (3-phenyl-2propenyloxy) pipehdino-1-carboxylate (0.314 g, 50% yield) as a yellow oil.

[1075] ¹ H NMR (CDCb) δ ppm:

[1076] 1.46 (9H, s), 1.48 - 1.59 (2H, m), 1.81 - 1.93 (2H, m), 3.01 - 3.15 (2H, m) ,

3.50 - 3.61 (1H, m), 3.74 - 3.87 (2H, m), 4.19 (2H, d, J = 5.9 Hz), 6.29 (1H, ddd, J = 5.9 Hz, 5.9 Hz, 15.9 Hz), 6.61 (1H, d, J = 15.9 Hz), 7.18 - 7.43 (5H, m).

Reference Example 111

Preparation of ter-butyl 4- (3-phenyl-2-propenyloxy) piperidine [1077] 4- (3-phenyl-2-propenyloxy) pipehdino-1-carboxylate (0.314 g, 0.989 mmol) prepared in Reference Example 110 it was dissolved in ethanol (10 ml), to which 6 N aqueous hydrochloric acid solution (3 ml, 18 mmol) was added, and the mixture was stirred at 60 ° C for 1 hour. The reaction mixture was neutralized with solution

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423/854 aqueous sodium hydroxide, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dried in vacuo giving 4- (3-phenyl-2-propenyloxy) piperidine (0.198 g, 92% yield) as a yellow oil.

[1078] ¹ H NMR (CDCb) δ ppm:

[1079] 1.40-1.57 (2H, m), 1.91 -2.02 (2H, m), 2.56-2.70 (2H, m), 3.12 (2H, ddd,

J = 4.2 Hz, 4.2 Hz, 12.8 Hz), 3.42 - 3.52 (1H, m), 4.19 (2H, d, J = 5.9 Hz), 6.30 (1H, ddd, J = 5.9 Hz, 5.9 Hz, 15.9 Hz), 6.57 (1H, d, J = 15.9 Hz), 7.20 - 7.43 (5H, m ). Reference Example 112

Preparation of ter-butyl 4- [3- (4-chlorophenyl) -2-propenyloxy] piperidine-1-carboxylate [1080] 4-hydroxypiperidine-1-carboxylate (3.58 g, 17.8 mmol ) was dissolved in DMF (30 ml), to which sodium hydride (0.71 g, 17.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours.

[1081] On the other hand, 4-chlorokynamyl alcohol (3.00 g, 17.8 mmol) was dissolved in methylene chloride (60 ml), to which was added by dripping triethyl amine (5 ml, 35.6 mmol) ) and methanesulfonyl chloride (2.1 ml, 26.7 mmol) while cooling in an ice bath, the mixture was stirred at room temperature for 1.5 hours. Water was added to the mixture, which was extracted with methylene chloride, and the extract was washed with dilute hydrochloric acid solution, aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (10 ml).

[1082] Both DMF solutions were combined while cooling in an ice bath, and the mixture was stirred overnight. After [this] the reaction mixture was diluted with ethyl acetate, the mixture was washed with water and brine. The organic layer was dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 6/1) giving 4- [3- (4-chlorophenyl) -2propenyloxy] piperidine-1-carboxylate tert-butyl (0.759 g, 12% yield) as

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424/854 a yellow oil.

[1083] ¹ H NMR (CDCb) δ ppm:

[1084] 1.46 (9H, s), 1.50 - 1.62 (2H, m), 1.83 - 1.94 (2H, m), 3.03 - 3.14 (2H, m) ,

3.53-3.58 (1H, m), 3.77 -3.83 (2H, m), 4.17 (1H, d, J = 5.7 Hz), 4.18 (1H, d, J = 5.7 Hz), 6.27 (1H, ddd, J = 5.7 Hz, 5.7 Hz, 15.9 Hz), 6.57 (1H, d, J = 15.9 Hz), 7.20 - 7.33 (4H, m).

Reference Example 113

Preparation of terbutyl 4- [3- (4-chlorophenyl) -2-propenyloxy] piperidine [1085] Using 4- [3- (4-chlorophenyl) -2-propenyloxy] piperidine-1-carboxylate (0.350 g, 0.995 mmol ) prepared in Reference Example 112, 4- [3- (4-chlorophenyl) -2-propenyloxy] piperidine (0.291 g, quantitative) was prepared as a brown oil in the same manner as described in Reference Example 111.

[1086] ¹ H NMR (CDCb) δ ppm:

[1087] 1.38-1.56 (2H, m), 1.91 -2.01 (2H, m), 2.55 - 2.69 (2H, m), 3.11 (2H, ddd,

J = 4.0 Hz, 4.0 Hz, 13.0 Hz), 3.39 - 3.51 (1H, m), 4.18 (2H, d, J = 5.8 Hz), 6.28 (1H, ddd, J = 5.8 Hz, 5.8 Hz, 15.9 Hz), 6.57 (1H, d, J = 15.9 Hz), 7.25 - 7.35 (4H, m ). Reference Example 114

Preparation of tert-butyl 4- [3- (4-chlorophenyl) propoxy] piperidine-1-carboxylate [1088] A mixture of 4- [3- (4-chlorophenyl) -2-propenyloxy] piperidine-1-carboxylate tert-butyl (0.37 g, 1.05 mmol) prepared in Reference Example 112 and platinum oxide (37 mg) in ethanol (10 ml), was stirred at room temperature under atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 4/1) giving 4- [3- (4chlorophenyl) propoxy] piperidine-1-carboxylate tert-butyl (0.151 g , 40% yield) as a yellow oil.

[1089] ¹ H NMR (CDCb) δ ppm:

[1090] 1.40 - 1.51 (2H, m), 1.46 (9H, s), 1.77 - 1.90 (4H, m), 2.67 (2H, t, J = 7, 9 Hz), 3.02 - 3.12 (2H, m), 3.38 - 3.45 (3H, m), 3.73 - 3.79 (2H, m), 7.11 (2H, d , J = 8.4 Hz), 7.24 (1H, d, J = 8.4 Hz).

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425/854

Reference Example 115

Preparation of tert-butyl 4- [3- (4-chlorophenyl) propoxy] piperidine [1091] 4- [3- (4-chlorophenyl) propoxy] piperidine-1-carboxylate (0.151 g, 0.427 mmol) prepared in Example reference 114 was dissolved in methylene chloride (4 ml), to which trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride twice. The extracts were combined and washed with brine. The organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dried in vacuo giving 4- [3- (4-chlorophenyl) propoxy] piperidine (0.109 g, 92% yield) as a brown oil. [1092] ¹ H NMR (CDCb) δ ppm:

[1093] 1.35 -1.51 (2H, m), 1.83-1.94 (4H, m), 2.54-2.70 (4H, m), 3.03 - 3.14 ( 2H,

m), 3.22 - 3.38 (1H, m), 3.43 (2H, t, J = 6.3 Hz), 7.12 (2H, d, J = 8.4 Hz), 7, 25 (2H, d, J = 8.4 Hz).

Reference Example 116

Preparation of tert-butyl 4- [2- (4-chlorophenyl) ethoxy] piperidine-1-carboxylate [1094] (4-chlorobenzyl) triphenyl phosphonium chloride (1.191 g, 2.81 mmol) was dissolved in DMSO (20 ml), to which sodium hydride (0.118 g, 2.95 mmol) was added while cooling in an ice bath, and the mixture was stirred at room temperature for 1 hour. Tert-butyl 4-formyloxypiperidine-1-carboxylate (0.500 g,

2.34 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature overnight. After the reaction mixture was diluted with ethyl acetate, the mixture was washed with water and brine. The organic layer was dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / hexane = 9/1) giving a colorless oil.

[1095] Using oil thus obtained, tert-butyl 4- [2- (4-chlorophenyl) ethoxy] piperidine-1-carboxylate (0.127 g, 16% yield) was prepared as a colorless oil in the same manner as described in Reference Example 114.

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426/854 [1096] ¹ H NMR (CDCb) δ ppm:

[1097] 1.40-1.51 (2H, m), 1.45 (9H, s), 1.71-1.79 (2H, m), 2.83 (2H, t, J = 6, 9 Hz),

3.02 - 3.13 (2H, m), 3.38 - 3.44 (1H, m), 3.62 - 3.75 (4H, m), 7.15 (2H, d, J = 8 , 5 Hz), 7.25 (2H, d, J = 8.5 Hz).

Reference Example 117

Preparation of 4- [2- (4-chlorophenyl) ethoxy] piperidine [1098] Using tert-butyl 4- [2- (4-chlorophenyl) ethoxy] piperidine-1-carboxylate (0.127 g, 0.374 mmol) prepared in the Example Reference 116, 4- [2- (4-chlorophenyl) ethoxy] piperidine (0.080 g, 89% yield) was prepared as a colorless oil in the same manner as described in Reference Example 115.

[1099] ¹ H NMR (CDCb) δ ppm:

[1100] 1.37 - 1.48 (2H, m), 1.84 - 1.91 (2H, m), 2.53-2.63 (2H, m), 2.83 (2H, t, J = 7.0 Hz), 3.01 -3.09 (2H, m), 3.25-3.41 (1H, m), 3.64 (2H, t, J = 7.0 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz).

Reference Example 118

Preparation of 1- (2-nitrovinyl) -4-trifluoromethylbenzene [1101] 4-trifluoromethylbenzaldehyde (3.00 g, 17.2 mmol) was dissolved in nitromethane (10 ml), to which was added ammonium acetate (1.341 g, 17.4 mmol), and the mixture was heated to reflux for 2 hours. Water was added to the mixture, which was extracted with methylene chloride twice, and the extracts were combined and washed with brine, and dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 9/1) giving 1- (2-nitrovinyl) -4-trifluoromethylbenzene (1.596 g, 43% yield) as a yellow powder crystal clear.

[1102] ¹ H NMR (CDCb) δ ppm:

[1103] 7.58-7.74 (5H, m), 8.02 (1H, d, J = 13.8 Hz).

Reference Example 119

Preparation of 2- (4-trifluoromethylphenyl) ethylamine [1104] Lithium aluminum hydride (0.558 g, 14.7 mmol) was suspended in THF (10

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427/854 ml), to which the solution of 1- (2-nitrovinyl) -4trifluoromethylbenzene (1,596 g, 7.35 mmol) prepared in Reference Example 118 in THF (10 ml) was added by dripping while cooling in a ice bath, and the mixture was heated to reflux for 2 hours. Methanol was added slowly to the mixture until defoaming ceased. Water (0.6 ml), 15% aqueous sodium hydroxide solution (0.6 ml) and water (1.8 ml) were added in this order, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with an amine-treated surface (Fuji Silysia; NH-DM1020 solvent; methylene chloride / n-hexane = 4/1) giving 2- (4-trifluoromethylphenyl) ethylamine (0.431 g, 31% yield) as an orange oil.

[1105] ¹ H NMR (CDCb) δ ppm:

[1106] 2.81 (2H, t, J = 6.9 Hz), 3.03 (2H, t, J = 6.9 Hz), 7.32 (2H, d, J = 8.0 Hz) ,

7.56 (2H, d, J = 8.0 Hz).

Reference Example 120

Preparation of N- (1-benzylpiperidin-4-yl) -N- [2- (4-trifluoromethylphenyl) ethyl] ter-butyl carbamate [1107] 2- (4-trifluoromethylphenyl) ethylamine (0.431 g, 2.28 mmol ) prepared in Reference Example 119 and 1-benzyl-4-piperidone (0.517 g, 2.73 mmol) were dissolved in methanol (15 ml), to which sodium cyanoborohydride (0.429 g, 6.83 mmol) was added and acetic acid (0.52 ml, 9.11 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), to which was added di-tert-butyl dicarbonate (0.597 g, 2.74 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with brine. The organic layer was dried over sodium sulfate, and then filtered, and the filtrate was concentrated under pressure

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428/854 reduced. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/1) giving N- (1-benzylpiperidin-4-yl) -N- [2- (4trifluoromethylphenyl) ethyl] tert-butyl carbamate (0.437 g, 41% yield) as a colorless oil.

[1108] ¹ H NMR (CDCb) δ ppm:

[1109] 1.55 (9H, s), 1.59 - 1.73 (4H, m), 1.90-2.10 (2H, m), 2.82 -2.96 (4H, m) ,

3.24 - 3.28 (2H, m), 3.49 (2H, s), 4.00 (1H, bs), 7.26 - 7.31 (7H, m), 7.54 (2H, d, J = 8.0 Hz).

Reference Example 121

Preparation of N- (piperidin-4-yl) -N- [2- (4-trifluoromethylphenyl) ethyl] ter-butyl carbamate [1110] A mixture of N- (1-benzylpiperidin-4-yl) -N- [ 2- (4trifluoromethylphenyl) ethyl] tert-butyl carbamate (0.437 g, 0.944 mmol) prepared in Reference Example 120 and 20% palladium / carbon hydroxide (100 mg) in ethanol (20 ml) was stirred at room temperature under an atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure giving tert-butyl N- (piperidin-4-yl) -N- [2- (4trifluoromethylphenyl) ethyl] carbamate (0.332 g, yield 94%) as a colorless oil.

[1111] ¹ H NMR (CDCb) δ ppm:

[1112] 1.49 (9H, s), 1.51 - 1.80 (4H, m), 2.62 - 3.49 (9H, m), 7.28 - 7.31 (2H, m) ,

7.54 (2H, d, J = 8.0 Hz).

Reference Example 122

Preparation of ter-butyl 4- (4-trifluoromethylbenzyloxy) pipendin-1-carboxylate [1113] 4-hydroxypiperidine-1-carboxylate (1.88 g, 9.34 mmol) was dissolved in THF (20 ml ). Sodium hydride (411 mg, 10.3 mmol) was added to this solution while cooling in an ice bath, and the mixture was stirred for 1 hour. 4- (Trifluoromethyl) benzylbromide (2.23 g, 9.34 mmol) was added to the mixture, which was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. O

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429/854 residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving tert-butyl 4- (4-trifluoromethylbenzyloxy) pipendino-1-carboxylate (2.56 g, 76% yield) as a light yellow oil.

[1114] ¹ H NMR (CDCb) δ ppm:

[1115] 1.46 (9H, s), 1.51 - 1.67 (2H, m), 1.83 - 1.91 (2H, m), 3.07 - 3.18 (2H, m) ,

3.52 - 3.63 (1H, m), 3.73 - 3.83 (2H, m), 4.61 (2H, m), 7.46 (2H, d, J = 8.2 Hz) , 7.60 (2H, d, J = 8.2 Hz).

[1116] Using a corresponding starting material, a compound of Reference Example 123 was prepared in the same manner as described in Reference Example 122.

Reference Example 123

Tert-butyl 4- (4-trifluoromethoxybenzyloxy) pipendino-1-carboxylate [1117] a 74% yield [1118] ¹ H NMR (CDCb) δ ppm:

[1119] 1.46 (9H, s), 1.51 - 1.65 (2H, m), 1.82 - 1.90 (2H, m), 3.06 - 3.17 (2H, m) ,

3.52-3.62 (1H, m), 3.73-3.83 (2H, m), 4.54 (2H, s), 7.17-7.20 (2H, m), 7, 35-7.38 (2H, m).

Reference Example 124

Preparation of tert-butyl 4- (4-trifluoromethylbenzyloxy) pipendin [1120] 4- (4-trifluoromethylbenzyloxy) pipendin-1-carboxylate (2.56 g, 7.12 mmol) prepared in Reference Example 122 was dissolved in chloride methylene (20 ml), to which trifluoroacetic acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. This solution was neutralized with aqueous sodium hydroxide solution and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving 4- (4-trifluoromethylbenzyloxy) piperidine (1.85 g, 99% yield) as a white powder.

[1121] ¹ H NMR (CDCb) δ ppm:

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430/854 [1122] 1.46 - 1.60 (2H, m), 1.87 (1H, s), 1.93-2.01 (2H, m), 2.58 -2.69 (2H , m),

3.07 - 3.16 (2H, m), 3.43 - 3.54 (1H, m), 4.61 (2H, s), 7.44 - 7.48 (2H, m), 7, 57 - 7.61 (2H, m).

[1123] Using corresponding starting materials, compounds of Reference Examples 125 to 128 were prepared in the same manner as described in Reference Example 124.

Reference Example 125

4- (4-trifluoromethoxybenzyloxy) pipendin [1124] a white powder, 74% yield [1125] ¹ H NMR (CDCb) δ ppm:

[1126] 1.45 - 1.60 (2H, m), 1.92 -2.02 (2H, m), 2.11 (1H, s), 2.59 -2.70 (2H, m) ,

3.07-3.17 (2H, m), 3.43-3.54 (1H, m), 4.55 (2H, s), 7.17-7.20 (2H, m), 7, 35-7.40 (2H, m).

Reference Example 126

4- (4-chlorobenzyloxy) piperidine [1127] a white powder, 94% yield [1128] ¹ H NMR (CDCb) δ ppm:

[1129] 1.39-1.56 (3H, m), 1.90 -1.99 (2H, m), 2.55-2.66 (2H, m), 3.06-3.11 ( 2H,

m), 3.39 - 3.51 (1H, m), 4.52 (2H, s), 7.25 - 7.33 (4H, m).

Reference Example 127

4- (3,4-dichlorobenzyloxy) piperidine [1130] a white powder, 99% yield [1131] ¹ H NMR (CDCb) δ ppm:

[1132] 1.45 - 1.60 (2H, m), 1.91 - 2.01 (2H, m), 2.19 (1H, s), 2.59 - 2.70 (2H, m) ,

3.07 - 3.16 (2H, m), 3.42 - 3.52 (1H, m), 4.50 (2H, s), 7.17 (1H, dd, J = 1.9 Hz, 8.2 Hz), 7.40 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 1.9 Hz).

Reference Example 128

4- (4-phenylbenzyloxy) piperidine [1133] a white powder, 16% yield [1134] ¹ H NMR (CDCb) δ ppm:

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431/854 [1135] 1.45 - 1.60 (2H, m), 1.72 (1H, s), 1.95 -2.02 (2H, m), 2.57 -2.68 (2H , m),

3.07 - 3.16 (2H, m), 3.45 - 3.56 (1H, m), 4.60 (2H, s), 7.25 - 7.60 (9H, m).

Reference Example 129

Preparation of (1-benzylpiperidin-4-yl) - (4-trifluoromethoxyphenyl) amine [1136] A mixture of 1-bromo-4-trifluoromethoxybenzene (2.0 g, 8.3 mmol), 4 amino-1-benzylpiperidine (1 , 73 g, 9.13 mmol), palladium acetate (37 mg, 0.17 mmol), (R) - (+) - BINAP (155 mg, 0.25 mmol) and sodium ter-butoxide (1, 2 g, 11.6 mmol) in toluene (30 ml) was refluxed under a nitrogen atmosphere for 5 hours. Ethyl acetate and water were added to the reaction mixture while stirring, insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving (1-benzylpiperidin-4-yl) - (4trifluoromethoxyphenyl) amine ( 3.0 g, 99% yield) as a dark oil.

[1137] ¹ H NMR (CDCb) δ ppm:

[1138] 1.39 -1.55 (2H, m), 1.98 - 2.05 (2H, m), 2.09 - 2.20 (2H, m), 2.80 - 2.89 ( 2H,

m), 3.21 - 3.28 (1H, m), 3.52 (2H, s), 3.52 - 3.59 (1H, m), 6.48 - 6.55 (2H, m) , 6.98 7.02 (2H, m), 7.22 - 7.33 (5H, m).

Reference Example 130

Preparation of piperidin-4-yl- (4-fluoro-methoxyphenyl) amine [1139] A mixture of (1-benzylpiperidin-4-yl) - (4-fluoro-methoxyphenyl) amine (3.0 g,

8.3 mmol) prepared in Reference Example 129 and a catalytic amount of 10% palladium / carbon in ethanol (30 ml) was refluxed under atmospheric pressure of hydrogen for 20 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) giving piperidin-4-yl- (4-fluoromethoxyphenyl) amine (2.02 g, 94% yield) as a colorless crystalline powder.

[1140] ¹ H NMR (CDCb) δ ppm:

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432/854 [1141] 1.24 -1.39 (2H, m), 2.03 - 2.08 (2H, m), 2.65 - 2.77 (2H, m), 3.08 - 2 , 16 (2H,

m), 3.24 - 3.41 (1H, m), 3.59 (1H, br), 6.50 - 6.58 (2H, m), 6.99 - 7.03 (2H, m) . Reference Example 131

Preparation of tert-butyl 4- (4-chlorophenylamino) piperidine-1-carboxylate [1142] A mixture of ter-butyl p-bromochlorobenzene (1.91 g, 9.99 mmol), 4-aminopiperidine-1-carboxylate (2 , 0 g, 9.99 mmol), palladium acetate (45 mg, 0.2 mmol), (R) - (+) - BINAP (187 mg, 0.3 mmol) and sodium ter-butoxide (1, 35 g, 14.0 mmol) in toluene (20 ml) was refluxed under a nitrogen atmosphere for 1 hour. Ethyl acetate and water were added to the reaction mixture while stirring, insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving tert-butyl 4- (4-chlorophenylamino) piperidine1-carboxylate ( 2.67 g, 86% yield) as a yellow powder.

[1143] ¹ H NMR (CDCb) δ ppm:

[1144] 1.21 - 1.54 (2H, m) 1.46 (9H, s), 1.99 - 2.05 (2H, m), 2.85 - 2.97 (2H, m),

3.37 (1H, br), 3.51 (1H, br), 4.01 - 4.07 (2H, m), 6.48 - 6.54 (2H, m), 7.07 - 7, 14 (2H, m).

[1145] Using corresponding starting materials, compounds of Reference Examples 132 to 133 were prepared in the same manner as described in Reference Example 131.

Reference Example 132

4- (4-trifluoromethylphenylamino) terp-butyl-1-carboxylate [1146] a yellow powder, 93% yield [1147] ¹ H NMR (CDCb) δ ppm:

[1148] 1.21 - 1.58 (2H, m), 1.47 (9H, s), 2.00 -2.06 (2H, m), 2.88 -2.99 (2H, m) ,

3.47 (1H, br), 3.88 (1H, bs), 4.03 - 4.09 (1H, m), 6.56 (2H, d, J = 8.6 Hz), 7.39 (2H, d, J = 8.6 Hz).

Reference Example 133

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433/854

Tert-butyl 4- (4-cyanophenylamino) piperidine-1-carboxylate [1149], 92% yield [1150] ¹ H NMR (CDCb) δ ppm:

[1151] 1.26 - 1.54 (2Η, m), 1.47 (9H, s), 1.99 -2.05 (2H, m), 2.87 -2.99 (2H, m) ,

3.41 - 3.53 (1H, br), 4.02 - 4.14 (3H, m), 6.52 - 6.58 (2H, m), 7.39 - 7.45 (2H, m ). Reference Example 134

Preparation of tert-butyl 4- (4-chlorophenylamino) piperidine [1152] 4- (4-chlorophenylamino) piperidine-1-carboxylate (2.67 g, 8.59 mmol) prepared in Reference Example 131 was dissolved in chloride methylene (20 ml), to which trifluoroacetic acid (15 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. This solution was neutralized with aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving 4- (4-chlorophenylamino) piperidine as a light yellow powder.

[1153] ¹ H NMR (CDCb) δ ppm:

[1154] 1.22 -1.38 (2H, m), 2.02 - 2.07 (2H, m), 2.65 - 2.76 (2H, m), 3.08 - 3.16 ( 2H,

m), 3.25 - 3.38 (1H, m), 3.50 - 3.54 (1H, m), 6.48 - 6.55 (2H, m), 7.06 - 7.26 ( 2H, m).

[1155] Using corresponding starting materials, compounds of Reference Examples 135 to 136 were prepared in the same manner as described in Reference Example 134.

Reference Example 135

4- (4-trifluoromethylphenylamino) pipendin [1156] a yellow powder, 97% yield [1157] ¹ H NMR (CDCb) δ ppm:

[1158] 1.26-1.42 (2H, m), 2.04 - 2.09 (2H, m), 2.67-2.78 (2H, m), 3.09 - 3.17 ( 2H,

m), 3.34 - 3.46 (1H, m), 3.86 - 3.90 (1H, m), 6.59 (2H, d, J = 8.6 Hz), 7.38 (2H , d, J = 8.6 Hz).

Reference Example 136

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434/854

4- (4-cyanophenylamino) piperidine [1159] a yellow powder, 98% yield [1160] ¹ H NMR (CDCb) δ ppm:

[1161] 1.27 -1.45 (2H, m), 2.02 - 2.07 (2H, m), 2.67-2.78 (2H, m), 3.09 - 3.17 ( 2H,

m), 3.34 - 3.46 (1H, m), 4.09 - 4.13 (1H, m), 6.51 - 6.57 (2H, m), 7.38 - 7.44 ( 2H, m). Reference Example 137

Preparation of tert-butyl 4- (toluene-4-sulfonyloxy) piperidine-1-carboxylate [1162] 4-hydroxypiperidine-1-carboxylate (2.22 g, 10.0 mmol) was dissolved in acetonitrile ( 40 ml), to which were added triethylamine (2.74 ml, 19.7 mmol) and N, N, N ', N'-tetramethyl-1,6-diaminohexane (0.57 ml, 2.64 mmol), and the mixture was cooled in an ice bath. P-Toluenesulfonyl chloride (2.75 g, 14.4 mmol) was added to this mixture, which was allowed to return to room temperature and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving tert-butyl 4- (toluene-4-sulfonyloxy) piperidine-1-carboxylate (4.16 g, 89% yield) as a light yellow powder.

[1163] ¹ H NMR (CDCb) δ ppm:

[1164] 1.44 (9H, s), 1.64 - 1.82 (4H, m), 2.44 (3H, s), 3.19 - 3.30 (2H, m), 3.54 -

3.64 (2H, m), 4.63 - 4.72 (1H, m), 7.31 - 7.37 (2H, m), 7.78 - 7.82 (2H, m).

Reference Example 138

Preparation of tert-butyl 4- (4-trifluoromethoxyphenylsulfanyl) pipendin-1-carboxylate [1165] 4- (Trifluoromethoxy) thiophenol (2.0 g, 10.3 mmol) was dissolved in THF (30 ml), and this solution it was cooled in an ice bath. Sodium hydride (453 mg, 11.3 mmol) was added thereto, and the mixture was stirred for 30 minutes. Thereto-butyl 4- (toluene-4-sulfonyloxy) piperidine-1-carboxylate (3.66 g, 10.3 mmol) prepared in Reference Example 137, and the resulting mixture was stirred at room temperature for 30 minutes, and then heated to reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloride

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435/854 methylene. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (n-hexane / ethyl chloride = 20/1) giving 4- (4trifluoromethoxyphenylsulfanyl) pipendino-1-carboxylate tert-butyl (3.12 g, yield of 80%) as a colorless oil.

[1166] ¹ H NMR (CDCb) δ ppm:

[1167] 1.45 (9H, s), 1.46 - 1.60 (2H, m), 1.87 - 1.95 (2H, m), 2.86 -2.98 (2H, m) ,

3.14 - 3.23 (1H, m), 3.94 - 4.00 (2H, m), 7.13 - 7.17 (2H, m), 7.40 - 7.47 (2H, m ). Reference Example 139

Preparation of 4- (4-trifluoromethoxyphenylsulfanyl) pipendin [1168] Using terbutyl 4- (4-trifluoromethoxyphenylsulfanyl) pipendino-1-carboxylate prepared in Reference Example 138, 4- (4trifluoromethoxyphenylsulfanyl) pipendine (92% yield) was prepared as a colorless oil in the same manner as described in Reference Example 134.

[1169] ¹ H NMR (CDCb) δ ppm:

[1170] 1.43-1.59 (2H, m), 1.91 -1.98 (2H, m), 2.59-2.70 (2H, m), 3.06 - 3.20 ( 3H,

m), 7.12-7.16 (2H, m), 7.40 - 7.46 (2H, m).

Reference Example 140

Preparation of tert-butyl 4- (4-trifluoromethoxybenzyl) pipendin-1-carboxylate [1171] Triphenyl- (4-fluoromethoxybenzyl) phosphonium bromide (2.0 g, 3.87 mmol) was dissolved in DMSO (20 ml) , to which sodium hydride (168 mg, 4.2 mmol) was added, and the mixture was stirred for 30 minutes. To the mixture tert-butyl 4-oxopiperidine-1-carboxylate (700 mg, 3.51 mmol) was added, and the resulting mixture was stirred at 60 ° C for 2 hours. The reaction mixture was poured into water, and extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving a colorless crystalline powder.

[1172] A mixture of this intermediate and a catalytic amount of 10% Pd / C in methanol (30 ml) was stirred at room temperature under a pressure

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436/854 atmospheric hydrogen for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure giving tert-butyl 4- (4-trifluoromethoxybenzyl) pipendino-1-carboxylate (1.28 g, 60% yield) as a colorless oil.

[1173] ¹ H NMR (CDCb) δ ppm:

[1174] 1.06 - 1.21 (2H, m), 1.45 (9H, s), 1.57 - 1.70 (3H, m), 2.52 -2.69 (4H, m) ,

4.08 (2H, br), 7.09-7.17 (4H, m).

Reference Example 141

Preparation of 4- (4-trifluoromethoxybenzyl) pipendin [1175] Using tert-butyl 4- (4-trifluoromethoxybenzyl) pipendino-1-carboxylate prepared in Reference Example 140, 4- (4trifluoromethoxybenzyl) pipendin was prepared in the same manner as described in Reference Example 134.

[1176] Colorless solid, 99% yield [1177] ¹ H NMR (CDCb) δ ppm:

[1178] 1.06 - 1.22 (2H, m), 1.50 (1H, s), 1.53 - 1.68 (3H, m), 2.48 -2.60 (4H, m) ,

3.02 - 3.08 (2H, m), 7.09 - 7.17 (4H, m).

Reference Example 142

Preparation of 1-benzyl-4- (4-trifluoromethoxybenzylidene) piperidine [1179] Triphenyl- (4-trifluoromethoxybenzyl) phosphonium bromide (21.6 g, 41.75 mmol) was dissolved in DMSO (110 ml), which sodium hydride (1.82 g, 45.52 mmol) was added, and the mixture was stirred for 30 minutes. 1-Benzyl-4piperidone (7.18 g, 37.96 mmol) was added to the mixture, and the resulting mixture was stirred at 60 ° C for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) giving 1-benzyl-4- (4trifluoromethoxybenzylidenejpiperidine (9.75 g, 74% yield) as an oil yellow.

[1180] ¹ H NMR (CDCb) δ ppm:

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437/854 [1181] 2.36-2.55 (8H, m), 3.53 (2H, s), 6.23 (1H, s), 7.11 -7.34 (9H, m).

[1182] Using a corresponding starting material, a compound of Reference Example 143 was prepared in the same manner as described in Reference Example 142.

Reference Example 143

1-benzyl-4- (4-trifluoromethylbenzylidene) pipendin [1183] a yellow oil, 52% yield [1184] ¹ H NMR (CDCb) δ ppm:

[1185] 2.38-2.57 (8H, m), 3.53 (2H, s), 6.28 (1H, m), 7.24-7.56 (9H, m).

Reference Example 144

Preparation of 4- (4-trifluoromethoxybenzyl) pipendin (an alternative method for synthesis of the compound in Reference Example 141) [1186] A mixture of 1-benzyl-4- (4-trifluoromethylbenzylidene) piperidine (9.7 g, 27, 92 mmol) prepared in Reference Example 142, 6 N hydrochloric acid (9.3 ml), and 10% palladium / carbon (970 mg) in ethanol (100 ml) was stirred at 50 ° C under atmospheric pressure of hydrogen for 5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water and 10% aqueous sodium hydroxide solution were added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving 4- (4-trifluoromethoxybenzyl) pipendin (6.77 g, 94% yield) as a colorless crystalline powder.

[1187] ¹ H NMR (CDCb) δ ppm:

[1188] 1.06 - 1.22 (2H, m), 1.50 (1H, s), 1.53 - 1.68 (3H, m), 2.48 -2.60 (4H, m) ,

3.02 - 3.08 (2H, m), 7.09 - 7.17 (4H, m).

[1189] Using corresponding starting materials, compounds of Reference Examples 145 and 146 were prepared in the same manner as described in Reference Example 144.

Reference Example 145

4- (4-trifluoromethylbenzyl) pipendin

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438/854 [1190] a colorless crystalline powder, 94% yield [1191] ¹ H NMR (CDCb) δ ppm:

[1192] 1.06-1.29 (2H, m), 1.50-1.69 (4H, m), 2.48 - 2.60 (4H, m), 3.02 - 3.09 ( 2H,

m), 7.23 - 7.29 (2H, m), 7.51 - 7.54 (2H, m).

Reference Example 146

4- (4-chlorobenzyl) piperidine [1193] a colorless crystalline powder, 94% yield [1194] ¹ H NMR (CDCb) δ ppm:

[1195] 1.07-1.21 (2H, m), 1.53-1.82 (4H, m), 2.47 - 2.59 (4H, m), 3.02 - 3.08 ( 2H,

m), 7.04 - 7.08 (2H, m), 7.22 - 7.27 (2H, m).

Reference Example 147 Preparation of 1-benzylpiperidine-4-carboxylic acid N-methyl-N-methoxyamide [1196] 1-Benzylpiperidine-4-carboxylic acid hydrochloride (21 g, 82.3 mmol) was suspended in chloroform, at DMF (1 ml) and thionyl chloride (30 ml) were added at room temperature, and the mixture was heated to reflux for 2 hours. The mixture was concentrated under reduced pressure to prepare acid chloride compound.

[1197] In another vessel, N, O-dimethylhydroxylamine hydrochloride (12 g, 0.12 mol) was dissolved in acetone (200 ml) -water (20 ml), to which was added potassium carbonate (34.12 g , 246, 9 mmol), and the mixture was stirred while cooling in an ice bath. A previously prepared solution of the acid chloride compound in acetone (120 ml) was added dropwise to this mixture, which was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, to which water was added, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving 1-benzylpiperidine-4-carboxylic acid N-methyl-Nmethoxyamide (16.8 g, 78% yield) as a brown oil.

[1198] ¹ H NMR (CDCl3) δ ppm:

[1199] 1.65 -1.92 (4H, m), 1.97 - 2.07 (2H, m), 2.62 - 2.68 (1H, m), 2.91 - 2.96 ( 2H,

m), 3.17 (3H, s), 3.51 (2H, s), 3.69 (3H, s), 7.20 - 7.32 (5H, m).

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439/854

Reference Example 148

Preparation of 1-benzyl-4- (4-trifluoromethoxybenzoyl) pipendin [1200] 1-Bromo-4-trifluoromethoxybenzene (5.3 g, 22.0 mmol) was dissolved in dry THF (70 ml) under an atmosphere of nitrogen, and this solution was cooled to -60 ° C. N-butyl lithium solution (1.6 M) hexane (15 ml, 24.0 mmol) was added dropwise to the solution, and the mixture was allowed to reach a temperature of -30 ° C and stirred for 1 hour. This mixture was again cooled to -60 ° C, to which a solution of N-methyl-N-methoxyamide of 1-benzylpiperidine-4-carboxylic acid (4.1 g, 15.6 mmol) prepared in the Reference Example was added dropwise. 147 in THF (10 ml), and the mixture was stirred for 1 hour and then at 0 ° C for 3 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and extracted with diethyl ether. The extract was washed with water and brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (nhexane / ethyl acetate = 4/1) giving 1-benzyl-4- (4-trifluoromethoxybenzoyl) pipendin (4.8 g, 85% yield) as a light yellow oil.

[1201] ¹ H NMR (CDCb) δ ppm:

[1202] 1.80-1.89 (4H, m), 2.04 - 2.18 (2H, m), 2.94-3.01 (2H, m), 3.15 - 3.24 ( 1H,

m), 3.55 (2H, s), 7.19 - 7.34 (7H, m), 7.95 - 8.01 (2H, m).

[1203] Using a corresponding starting material, a compound of Reference Example 149 was prepared in the same manner as described in Reference Example 148.

Reference Example 149

1-benzyl-4- (4-trifluoromethylbenzoyl) pipendin [1204] a light yellow oil, 66% yield [1205] ¹ H NMR (CDCb) δ ppm:

[1206] 1.78 -1.89 (4H, m), 2.09 - 2.19 (2H, m), 2.94 - 3.02 (2H, m), 3.16 - 3.29 ( 1H,

m), 3.55 (2H, m), 7.26 - 7.34 (5H, m), 7.70 - 7.74 (2H, m), 8.00 - 8.04 (2H, m) . Reference Example 150

Preparation of 4- (4-trifluoromethoxybenzoyl) pipendin

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440/854 [1207] 1-Benzyl-4- (4-trifluoromethoxybenzoyl) piperidine (4.8 g, 13.22 mmol) prepared in Reference Example 148 was dissolved in methylene chloride (60 ml), and this solution was cooled in an ice bath. Ethyl 2-chlorochloroformate (2.9 ml, 26.4 mmol) was added dropwise to the solution, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, methanol (100 ml) was added to the residue, and the resulting mixture was heated to reflux for 15 minutes. Water was added to the reaction mixture, which was stirred for 30 minutes, and neutralized with aqueous sodium hydroxide solution. The mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving 4- (4trifluoromethoxybenzoyl) piperidine (1.3 g, yield 36%) as a light orange crystalline powder.

[1208] ¹ H NMR (CDCb) δ ppm:

[1209] 1.57-1.88 (5H, m), 2.71 -2.81 (2H, m), 3.15-3.23 (2H, m), 3.29 - 3.42 ( 1H,

m), 7.27 - 7.28 (2H, m), 7.95 - 8.05 (2H, m).

[1210] Using corresponding starting materials, compounds of Reference Examples 151 and 152 were prepared in the same manner as described in Reference Example 150.

Reference Example 151

4- (4-trifluoromethylbenzoyl) pipendin [1211] a colorless crystalline powder, 68% yield [1212] ¹ H NMR (CDCb) δ ppm:

[1213] 1.61 -1.76 (3H, m), 1.82 -1.89 (2H, m), 2.72-2.83 (2H, m), 3.16 - 3.24 ( 2H,

m), 3.32 - 3.44 (1H, m), 7.72 - 7.76 (2H, m), 8.01 - 8.05 (2H, m).

Reference Example 152 4- (4-chlorobenzoyl) piperidine [1214] a colorless crystalline powder, 100% yield [1215] ¹ H NMR (CDCb) δ ppm:

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441/854 [1216] 1.60 -1.84 (5H, m), 2.72 - 2.83 (2H, m), 3.16 - 3.24 (2H, m), 3.30 - 3 , 40 (1H,

m), 7.41 - 7.47 (2H, m), 7.85 - 7.91 (2H, m).

Reference Example 153 Preparation of N- {2- [4- (4-trifluoromethylphenyl) piperazin-1-yl] ethyl} phthalimide [1217] A mixture of 1- (4-trifluoromethylphenyl) piperazine (5.2 g, 22, 59 mmol), N- (2bromoethyl) phthalimide (5.22 g, 20.53 mmol) and potassium carbonate (3.36 g, 24.28 mmol) in DMF (30 ml) was stirred at 100 ° C for 2 hours. The reaction mixture was allowed to return to room temperature, to which water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 50/1), and the resulting solid was washed with methanol, and then dried in vacuo giving N- {2- [4 - (4-trifluoromethylphenyl) piperazin-1-yl] ethyl} phthalimide (4.85 g, 53% yield) as a white powder.

[1218] ¹ H NMR (CDCb) δ ppm:

[1219] 2.64 - 2.72 (6H, m), 3.18 - 3.23 (4H, m), 3.86 (2H, t, J = 6.4 Hz), 6.89 (2H , d, J = 8.7 Hz), 7.45 (2H, d, J = 8.7 Hz), 7.70 - 7.75 (2H, m), 7.81 - 7.86 (2H, m). Reference Example 154 Preparation of 2- [4- (4-trifluoromethylphenyl) piperazin-1-yl] ethylamine [1220] N- {2- [4- (4-trifluoromethylphenyl) piperazin-1-yl] ethyl} phthalimide (4 g, 9.92 mmol) prepared in Reference Example 153 was suspended in ethanol (30 ml), to which hydrazine monohydrate (0.53 ml, 10.91 mmol) was added, and the mixture was heated to reflux for 5 hours. The reaction mixture was allowed to return to room temperature, and the resulting precipitates were collected by means of filtration. This was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 100/1) giving 2- [4- (4-trifluoromethylphenyl) piperazin-1yl] ethylamine (2.87 g, yield 100%) as a colorless crystalline powder.

[1221] ¹ H NMR (CDCb) δ ppm:

[1222] 1.33 (2H, bs), 2.49 (2H, t, J = 6.1 Hz), 2.59 - 2.63 (4H, m), 2.84 (2H, t, J =

6.1 Hz), 3.26 - 3.31 (4H, m), 6.92 (2H, d, J = 8.7 Hz), 7.48 (2H, d, J = 8.7 Hz) .

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442/854

Reference Example 155

Preparation of N- {2- [4- (4-trifluoromethylphenyl) piperazin-1-yl] ethyl} formamide [1223] A mixture of 2- [4- (4-trifluoromethylphenyl) piperazin-1-yl] ethylamine (906 mg , 3.32 mmol) prepared in Reference Example 154 and ethyl formate (10 ml) was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving N- {2- [4- (4-trifluoromethylphenyl) piperazin-1yl] ethyl} formamide (942 mg, 94% yield) as a white powder.

[1224] ¹ H NMR (CDCb) δ ppm:

[1225] 2.53 - 2.65 (6H, m), 3.26 - 3.31 (4H, m), 3.42 - 3.49 (2H, m), 6.05 (1H, bs) ,

6.92 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.7 Hz), 8.21 (1H, s).

Reference Example 156

Preparation of N-methyl- {2- [4- (4-trifluoromethylphenyl) piperazin-1-yl] ethyl} amine [1226] Lithium aluminum hydride (237 mg, 6.25 mmol) was suspended in THF (20 ml) , which was stirred while taking a bath in an ice bath. To this was added a solution of N- {2- [4- (4-trifluoromethylphenyl) piperazin-1-yl] ethyl} formamide (942 mg, 3.13 mmol) prepared in Reference Example 155 in THF ( 10 ml), and the mixture was stirred at room temperature for 2 hours and then heated to reflux for 2 hours. The reaction mixture was allowed to return to room temperature, to which water and a 15% aqueous solution of sodium hydroxide were carefully added. To the mixture, sodium sulfate was added, and the resulting mixture was vigorously stirred and filtered through Celite. The filtrate was concentrated under reduced pressure giving N-methyl- {2- [4- (4-thfluoromethylphenyl) piperazin-1] ethyl} amine (900 mg, 100% yield) as a yellow oil.

[1227] ¹ H NMR (CDCb) δ ppm:

[1228] 2.47 (3H, s), 2.52 - 2.74 (8H, m), 3.26 - 3.30 (4H, m), 3.71 - 3.77 (1H, m) ,

6.91 (2H, d, J = 8.7 Hz), 7.47 (2H, d, J = 8.7 Hz).

Reference Example 157

Preparation of ter-butyl 4- (2-methylaminoethyl) piperazine-1-carboxylate [1229] 4- (2-chloroethyl) piperazine-1-carboxylate (3.13 g, 12.58 mmol) was

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443/854 dissolved in methanol (20 ml), to which 40% methylamine methanol solution (30 ml) was added, and the mixture was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure giving tert-butyl 4- (2methylaminoethyl) piperazine-1-carboxylate (3.0 g, 98% yield) like a light yellow oil.

[1230] ¹ H NMR (CDCb) δ ppm:

[1231] 1.46 (9H, m), 1.66 (1H, s), 2.36 - 2.41 (4H, m), 2.45 (3H, s), 2.46 - 2.53 (2H,

m), 2.65 - 2.70 (2H, m), 3.40 - 3.44 (4H, m).

Reference Example 158

Preparation of N- [2- (4-trifluoromethylphenoxy) ethyl] phthalimide [1232] A mixture of N- (2-hydroxyethyl) phthalimide (3.59 g, 18.75 mmol), 4 hydroxybenzotrifluoride (3.04 g, 18, 75 mmol), diethyl azodicarboxylate (4.37 ml, 28.13 mmol) and triphenylphosphine (7.38 g, 28.13 mmol) in THF (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 5/1) giving N- [2- (4-trifluoromethylphenoxy) ethyl ] phthalimide (4.05 g, 69% yield) as a colorless crystalline powder.

[1233] ¹ H NMR (CDCb) δ ppm:

[1234] 4.11 -4.16 (2H, m), 4.25 - 4.30 (2H, m), 6.92-6.96 (2H, m), 7.48 - 7.52 ( 2H,

m), 7.72 - 7.77 (2H, m), 7.83 - 7.89 (2H, m).

Reference Example 159

Preparation of 2- (4-trifluoromethylphenoxy) ethylamine [1235] Using N- [2- (4-trifluoromethylphenoxy) ethyl] phthalimide prepared in Reference Example 158, 2- (4-trifluoromethylphenoxy) ethylamine was prepared in the same manner as described in Reference Example 154.

[1236] a colorless oil, 95% yield [1237] ¹ H NMR (CDCb) δ ppm:

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444/854 [1238] 1.36 (2H, s), 3.11 (2H, t, J = 5.1 Hz), 4.03 (2H, t, J = 5.1 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.6 Hz).

Reference Example 160

Preparation of N- [2- (4-trifluoromethylphenoxy) ethyl] formamide [1239] A mixture of 2- (4-trifluoromethylphenoxy) ethylamine (1.38 g, 6.72 mmol) prepared in Reference Example 159 and ethyl formate (10 ml) was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving N- [2- (4-trifluoromethylphenoxy) ethyl] formamide (1.51 g, 97% yield) as a white powder.

[1240] ¹ H NMR (CDCb) δ ppm:

[1241] 3.72-3.78 (2H, m), 4.09-4.13 (2H, m), 6.02 (1H, bs), 6.96 (2H, d, J = 8, 6

Hz), 7.56 (2H, d, J = 8.6 Hz), 8.24 (1H, s).

Reference Example 161

Preparation of N-methyl-N- [2- (4-trifluoromethylphenoxy) ethyl] amine [1242] N- [2- (4-trifluoromethylphenoxy) ethyl] formamide (2.02 g, 8.66 mmol) prepared in the Example Reference 160 was dissolved in THF (20 ml). Borane-THF complex solution (1 M) THF (21.7 ml, 21.7 mmol) was added dropwise to this solution while cooling in an ice bath, and the mixture was stirred overnight. . The reaction mixture was cooled, to which water and 6 N hydrochloric acid were added, and the mixture was stirred for 20 minutes. The reaction mixture was neutralized with an aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) giving N-methyl-N- [2- (4-trifluoromethylphenoxy) ethyl] amine (1.05 g, yield 55%) as a white powder.

[1243] ¹ H NMR (CDCb) δ ppm:

[1244] 2.68 (3H, d, J = 5.8 Hz), 3.05 - 3.28 (2H, m), 4.06 (1H, br), 4.10-4.18 (1H ,

m), 4.45 - 4.54 (1H, m), 6.98 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz).

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445/854

Reference Example 162

Preparation of N-methyl-N- [2- (4-trifluoromethoxyphenoxy) ethyl] amine [1245] 1- (2-Bromoethoxy) -4- (trifluoromethoxy) benzene (2.2 g, 7.72 mmol) was dissolved in methanol (20 ml), to which 40% methylamine methanol solution (20 ml) was added by dripping, and the mixture was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure giving N-methylN- [2- (4-trifluoromethoxyphenoxy) ethyl] amine (1.44 g, 79% yield) as a light yellow oil.

[1246] ¹ H NMR (CDCb) δ ppm:

[1247] 1.54 (1H, s), 2.51 (3H, s), 2.97 (2H, t, J = 5.1 Hz), 4.06 (2H, t, J = 5.1 Hz),

6.85 - 6.92 (2H, m), 7.10 - 7.17 (2H, m).

Reference Example 163

Preparation of N-methyl-N- [2- (4-trifluoromethylphenoxy) ethyl] amine [1248] Using 1- (2-bromoethoxy) -4- (trifluoromethyl) benzene, N-methylN- [2- (4 -trifluoromethylphenoxy) ethyl] amine in the same manner as described in Reference Example 162.

[1249] a white powder, 82% yield [1250] ¹ H NMR (CDCb) δ ppm:

[1251] 2.68 (3H, d, J = 5.8 Hz), 3.02 - 3.28 (2H, m), 3.92 - 4.18 (2H, m), 4.41 4, 54 (1H, m), 6.98 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz)

Reference Example 164

Preparation of N, N'-dimethyl-N- [4- (trifluoromethyl) phenyl] -1,2-ethylenediamine [1252] A mixture of 4-bromobenzotrifluoride (3.0 g, 13.3 mmol), N, N ' dimethylethylenediamine (9.4 g, 0.11 mol), palladium acetate (60 mg, 0.27 mmol), BINAP (250 mg, 0.40 mmol) and sodium ter-butoxide (1.80 g, 18, 7 mmol) in toluene (20 ml) was refluxed under an atmosphere of nitrogen for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was stirred for some time. At

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446/854 insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) giving N, N'-dimethyl-N- [4 (trifluoromethyl) phenyl ] -1,2-ethylenediamine (650 mg, 21% yield) as a light yellow oil.

[1253] ¹ H NMR (CDCb) δ ppm:

[1254] 1.53 (1H, s), 2.47 (3H, s), 2.82 (2H, t, J = 6.7 Hz), 3.02 (3H, s), 3.52 ( 2H, t,

J = 6.7 Hz), 6.74 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.8 Hz).

Reference Example 165

Preparation of tert-butyl N- [1- (4-chlorophenyl) piperidin-4-yl] -N-methylcarbamate [1255] A mixture of p-bromochlorobenzene (3.13 g, 16.3 mmol), (piperidin- 4-yl) tert-Butyl N-methylcarbamate (3.5 g, 10.8 mmol), palladium acetate (73 mg, 0.33 mmol), (S) - (-) - BINAP (305 mg, 0 , 49 mmol) and sodium tert-butoxide (2.2 g, 22.9 mmol) in toluene (30 ml) was refluxed under an atmosphere of nitrogen for 3 hours. Ethyl acetate and water were added to the reaction mixture, the mixture was stirred for some time. Insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) giving N- [1- (4-chlorophenyl) piperidin-4 -yl] -N-tert-butyl methylcarbamate (4.7 g, 89% yield) as a yellow powder.

[1256] ¹ H NMR (CDCb) δ ppm:

[1257] 1.47 (9H, s), 1.70 - 1.90 (4H, m), 2.73 - 2.82 (2H, m), 2.74 (3H, s), 3.64 3.71 (2H, m), 4.08 (1H, br), 6.81 -6.87 (2H, m), 7.15-7.22 (2H, m).

[1258] Using corresponding starting materials, compounds of Reference Examples 166 to 168 were prepared in the same manner as described in Reference Example 165.

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447/854

Reference Example 166

Ter- butyl N- [1 - (4-trifluoromethoxyphenyl) pipendin-4-yl] -N-methylcarbamate [1259] 88% yield [1260] ¹ H NMR (CDCb) δ ppm:

[1261] 1.48 (9H, s), 1.72 - 1.91 (4H, m), 2.76 (3H, s), 2.79 - 2.85 (2H, m), 3.67 3.73 (2H, m), 4.10 (1H, br), 6.86-6.93 (2H, m), 7.07-7.11 (2H, m).

Reference Example 167

N- [1 - (4-trifluoromethylphenyl) pipendin-4-yl] -N-tert-butyl methylcarbamate [1262] yield 91% [1263] ¹ H NMR (CDCb) δ ppm:

[1264] 1.47 (9H, s), 1.72 - 1.87 (4H, m), 2.74 (3H, s), 2.82 - 2.94 (2H, m), 3.83 3.89 (2H, m), 4.12 (1H, br), 6.92 (2H, d, J = 8.7 Hz), 7.46 (2H, d, J = 8.7 Hz).

Reference Example 168

N- [1 - (4-cyanophenyl) piperidin-4-yl] -N-tert-butyl methylcarbamate [1265] 73% yield [1266] ¹ H NMR (CDCb) δ ppm:

[1267] 1.47 (9H, s), 1.69 - 1.77 (4H, m), 2.73 (3H, s), 2.87 - 3.00 (2H, m), 3.89 -

3.97 (2H, m), 4.16 (1H, br), 6.84 - 6.89 (2H, m), 7.45 - 7.51 (2H, m).

Reference Example 169

Preparation of ter-butyl N- [1- (4-chlorophenyl) piperidin-4-yl] -N-methylamine [1268] N- [1- (4-chlorophenyl) piperidin-4-yl] -N-methylcarbamate ( 4.71 g, 14.5 mmol) prepared in Reference Example 165 was dissolved in methylene chloride (30 ml), to which was added by dripping trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. The solution was neutralized with aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving N- [1- (4-chlorophenyl) piperidin-4-yl] -N-methylamine (3.1 g, 95% yield) as a light brown oil.

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448/854 [1269] ¹ H NMR (CDCb) δ ppm:

[1270] 0.99 (1H, s), 1.38 - 1.54 (2H, m), 1.95 - 2.00 (2H, m), 2.44 - 2.54 (1H, m) ,

2.46 (3H, s), 2.71 - 2.82 (2H, m), 3.55 - 3.63 (2H, m), 6.81 - 6.87 (2H, m), 7.14 - 7.21 (2H, m).

[1271] Using corresponding starting materials, compounds of Reference Examples 170 to 172 were prepared in the same manner as described in Reference Example 169.

Reference Example 170

N- [1- (4-trifluoromethoxyphenyl) pipendin-4-yl] -N-methylamine [1272] a light brown powder, 100% yield [1273] ¹ H NMR (CDCb) δ ppm:

[1274] 0.96 (1H, s), 1.39 - 1.55 (2H, m), 1.96 - 2.02 (2H, m), 2.44 - 2.57 (1H, m) ,

2.47 (3H, s), 2.73 - 2.84 (2H, m), 3.58 - 3.66 (2H, m), 6.86 - 6.92 (2H, m), 7.05 - 7.10 (2H, m).

Reference Example 171

N- [1- (4-trifluoromethylphenyl) pipendin-4-yl] -N-methylamine [1275] a light brown powder, 100% yield [1276] ¹ H NMR (CDCb) δ ppm:

[1277] 0.96 (1H, s), 1.36 - 1.52 (2H, m), 1.96 - 2.02 (2H, m), 2.47 (3H, s), 2.50 2.62 (1H, m), 2.82 - 2.94 (2H, m), 3.72 - 3.80 (2H, m), 6.92 (2H, d, J = 8.8 Hz) , 7.45 (2H, d, J = 8.8 Hz).

Reference Example 172

N- [1- (4-cyanophenyl) piperidin-4-yl] -N-methylamine [1278] a light brown powder, 99% yield [1279] ¹ H NMR (CDCb) δ ppm:

[1280] 1.05 (1H, s), 1.34 - 1.49 (2H, m), 1.95 - 2.02 (2H, m), 2.47 (3H, s), 2.55 -

2.67 (1H, m), 2.90 - 3.01 (2H, m), 3.76 - 3.84 (2H, m), 6.82 - 6.90 (2H, m), 7, 43 - 7.50 (2H, m).

Reference Example 173

Preparation of benzyl N- (2-methyl-2-propenyl) carbamate

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449/854 [1281] 2-Methylamine hydrochloride (21.52 g, 0.2 mol) was dissolved in water (200 ml), to which benzyl chloroformate (37.53 g, 0.22 mol) was added, and the mixture was cooled in an ice bath. Sodium carbonate (46.63 g, 0.44 mol) was gradually added to this mixture, which was stirred at room temperature for 3 hours. After the reaction mixture was extracted with methylene chloride twice, the extracts were combined, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 7/1) giving benzyl N- (2-methyl-2propenyl) carbamate (41.58 g, quantitative) as a colorless oil.

[1282] ¹ H NMR (CDCb) δ ppm:

[1283] 1.74 (3H, s), 3.75 (2H, d, J = 6.2 Hz), 4.69 - 4.94 (2H, m), 5.13 (2H, s), 7.26

-7.39 (5H, m).

Reference Example 174

Production of 4-chlorobenzyl N- (2-methyl-2-propenyl) carbamate [1284] 4-chlorobenzyl alcohol (3.00 g, 21.0 mmol) and triphosgene (3.12 g, 10, 5 mmol) were dissolved in toluene (15 ml), to which N-ethyldiisopropylamine (3.6 ml, 21.0 mmol) was added while cooling in an ice bath, and the mixture was stirred for 1 hour. The reaction mixture was poured into water, and extracted with methylene chloride twice. The extracts were combined and dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. A solution of 2-methylylamine hydrochloride (2.49 g, 23.1 mmol) in water (40 ml) was added to the residue, to which sodium carbonate (5.15 g, 48.6 mmol) was added while cooled in an ice bath, and the mixture was stirred for 15 minutes. The reaction mixture was extracted with methylene chloride twice, and the extracts were combined, dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 10/1) giving 4-chlorobenzyl N- (2-methyl-2-propenyl) carbamate (4.06 g, 80% yield) as a colorless liquid.

[1285] ¹ H NMR (CDCb) δ ppm:

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450/854 [1286] 1.74 (3H, s), 3.74 (2H, d, J = 5.8 Hz), 4.73 - 4.91 (2H, m), 5.08 (2H, s), 7.26

-7.41 (4H, m).

Reference Example 175

Preparation of 4-fluorobenzyl N- (2-methyl-2-propenyl) carbamate [1287] 4-Fluorobenzyl alcohol (3.00 g, 23.8 mmol) was dissolved in THF (60 ml), to which was added 1, T-carbonyldiimidazole (4.05 g, 25.0 mmol) while cooling in an ice bath, and the mixture was stirred for 30 minutes. 2-Methyl methylamine hydrochloride (2.81 g, 26.2 mmol) and triethylamine (3.98 g, 28.5 mmol) were added to the mixture, which was stirred for 2 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride twice. The extracts were combined, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 10/1) giving 4-fluorobenzyl N- (2-methyl-2-propenyl) carbamate (4.69 g, 88% yield) as a colorless oil.

[1288] ¹ H NMR (CDCb) δ ppm:

[1289] 1.73 (3H, s), 3.74 (2H, d, J = 5.8 Hz), 4.55 - 4.95 (3H, m), 5.08 (2H, s), 6.95

-7.14 (2H, m), 7.27-7.41 (2H, m).

Reference Example 176

Preparation of 3-methoxymethoxy-2-methyl-1-propene [1290] Chloromethyl methyl ether (105 ml, 1386 mmol) and N-ethyldiisopropylamine (265 ml, 1525 mmol) were added to a solution of 2-methyl-2- propen-1-ol (50 g, 693 mmol) in THF (500 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and washed with diethyl ether, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with water, a saturated solution of sodium hydrogen carbonate and then water, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 3methoxymethoxy-2-methylpropene (9.7 g, 12% yield) as a colorless liquid.

[1291] ¹ H NMR (CDCb) δ ppm:

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451/854 [1292] 1.76 (3H, s), 3.39 (3H, s), 3.97 (2H, s), 4.65 (2H, s), 4.85 - 4.94 ( 1H, m),

4.98-5.06 (1H, m).

Reference Example 177

Preparation of 2-methoxymethoxymethyl-2-methyloxirane [1293] M-chloroperbenzoic acid (22.7 g, 92 mmol) was gradually added to a solution of 3-methoxymethoxy-2-methyl-1-propene (9.7 g, 84 mmol) prepared in Reference Example 176 in methylene chloride (200 ml) while cooling in an ice bath and the mixture was stirred at room temperature for 6 hours. Sodium hydrogen carbonate (14.1 g, 168 mmol), water and methylene chloride were added to the reaction mixture, which was stirred for some time. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution, aqueous sodium thiosulfate solution and then aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 2-methoxymethoxymethyl-2-methyloxirane (6.8 g, 62% yield) as a green oil.

[1294] ¹ H NMR (CDCb) δ ppm:

[1295] 1.40 (3H, S), 2.65 (1H, d, J = 4.9 Hz), 2.78 (1H, d, J = 4.9 Hz), 3.38 (3H, s),

3.53 (1H, d, J = 11.1 Hz), 3.62 (1H, d, J = 11.1 Hz), 4.65 (2H, s).

Reference Example 178

Preparation of tert-butyl 4- (4-chlorobenzyl) piperazine-1-carboxylate [1296] Potassium carbonate (1.45 g, 10.47 mmol) and 4-chlorobenzyl chloride (1.82 g, 8.86 mmol) were added to a solution of tert-butyl piperazine-1-carboxylate (1.5 g, 8.05 mmol) in DMF (10 ml), and the mixture was stirred at 50 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 4- (4chlorobenzyl) piperazine-1-carboxylate (2.50 g, quantitative) like a colorless oil.

[1297] ¹ H NMR (CDCb) δ ppm:

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452/854 [1298] 1.45 (9H, s), 2.36 (4H, t, J = 5.0 Hz), 3.42 (4H, t, J = 5.0 Hz), 3.46 (2H, s),

7.23-7.31 (4H, m).

Reference Example 179

Preparation of 1- (4-chlorobenzyl) piperazine [1299] Trifluoroacetic acid (8 ml) was added to a solution of tert-butyl 4- (4-chlorobenzyl) piperazine-1-carboxylate (2.50 g, 8.05 mmol ) prepared in Reference Example 178 in methylene chloride (16 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. Aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving 1- (4 chlorobenzyl) piperazine (1.70 g, quantitative) as a colorless oil.

[1300] ¹ H NMR (DMSO-de) δ ppm:

[1301] 2.55 - 2.74 (4H, m), 3.57 - 3.76 (6H, m), 7.35 - 7.45 (4H, m), 8.55 - 8.88 ( 1H, br).

Reference Example 180

Preparation of 1- (4-trifluoromethylbenzyl) piperazine [1302] Using tert-butyl 4- (4-trifluoromethylbenzyl) piperazine-1-carboxylate, 1- (4-trifluoromethylbenzyl) piperazine was prepared in the same manner as described in the Example of Reference 179.

[1303] 100% yield [1304] ¹ H NMR (CDCb) δ ppm:

[1305] 2.72 (4H, t, J = 4.9 Hz), 3.16 - 3.26 (4H, m), 3.62 (2H, s), 7.44 (2H, d, J =

8.1 Hz), 7.59 (2H, d, J = 8.1 Hz).

Reference Example 181

Preparation of 1- (4-trifluoromethoxybenzyl) piperazine [1306] Using tert-butyl 4- (4-trifluoromethoxybenzyl) piperazine-1-carboxylate, 1- (4-trifluoromethoxybenzyl) piperazine was prepared in the same manner as described in the Example Reference 179.

[1307] 100% yield

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453/854 [1308] ¹ H NMR (CDCb) δ ppm:

[1309] 2.70 (4H, t, J = 4.9 Hz), 3.19 (4H, t, J = 4.9 Hz), 3.56 (2H, s), 7.17 (2H, d, J = 7.9 Hz), 7.33 (2H, d, J = 7.9 Hz).

Reference Example 182

Preparation of 4- [4- (4-trifluoromethoxybenzyl) piperazin-1-yl] phenol [1310] 4- (4-hydroxyphenyl) piperazine (3 g, 16.8 mmol) and 4-trifluoromethoxy benzaldehyde (3.36 g, 17.7 mmol) were dissolved in methanol (60 ml) and methylene chloride (15 ml). Sodium cyanoborohydride (1.59 g, 25.3 mmol) and acetic acid (1.6 ml) were added to this solution while cooling in an ice bath, and the mixture was stirred for 2 hours. Saturated aqueous solution of sodium hydrogen carbonate and methylene chloride was added to the reaction mixture, which was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 4- [4- (4-trifluoromethoxybenzyl) piperazin-1-yl] phenol (3.36 g, yield 57%) as a colorless crystalline powder.

[1311] ¹ H NMR (CDCb) δ ppm:

[1312] 2.59 - 2.64 (4H, m), 3.05 - 3.10 (4H, m), 3.56 (2H, s), 4.90 - 5.40 (1H, br) ,

6.69 - 6.75 (2H, m), 6.79 - 6.85 (2H, m), 7.16 (2H, d, J = 8.4 Hz), 7.37 (2H, d, J = 8.4 Hz).

Reference Example 183

Preparation of 1- [4- (tetrahydropyran-2-yloxy) phenyl] -4- (4-trifluoromethoxyphenyl) piperazine [1313] A mixture of 1- (4-trifluoromethoxyphenyl) piperazine (4.4 g, 17.8 mmol) , 2 (4-bromophenoxy) tetrahydropyran (4.6 g, 17.8 mmol), palladium acetate (159 mg, 0.71 mmol), BINAP (666 mg, 1.07 mmol) and sodium ter-butoxide ( 2.2 g, 23.1 mmol) in toluene (40 ml) was refluxed under a nitrogen atmosphere for 5 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for some time. Insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was

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454/854 concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 20/1) giving 1- [4 (tetrahydropyran-2-yloxy) phenyl] -4- (4-trifluoromethoxyphenyl) piperazine (2.7 g, 35% yield) as a white powder.

[1314] ¹ H NMR (CDCb) δ ppm:

[1315] 1.54 - 2.05 (6H, m), 3.21 - 3.34 (8H, m), 3.55 - 3.64 (1H, m), 3.89 - 3.99 ( 1H,

m), 5.31 -5.34 (11-1, m), 6.90-7.03 (6H, m), 7.11 - 7.16 (2H, m).

[1316] This title compound was also prepared using the method described in Reference Example 185.

Reference Example 184

Preparation of 1- [4- (tetrahydropyran-2-yloxy) phenyl] piperazine [1317] A mixture of 2- (4-bromophenoxy) tetrahydropyran (7.8 g, 30.3 mmol), piperazine (15.7 g, 180 mmol), palladium acetate (136 mg, 0.61 mmol), BINAP (567 mg, 0.91 mmol) and sodium tert-butoxide (3.8 g, 39.4 mmol) in toluene (50 ml) it was refluxed under a nitrogen atmosphere for 2 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for some time. Insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (nhexane / ethyl acetate = 20/1) giving 1- [4- (tetrahydropyran-2-yloxy) phenyl] piperazine (6.8 g, 85% yield) as a light gray powder.

[1318] ¹ H NMR (CDCb) δ ppm:

[1319] 1.57 - 2.04 (6H, m), 3.00 - 3.06 (8H, m), 3.53 - 3.66 (1H, m), 3.89 - 3.99 ( 1H,

m), 5.29 - 5.32 (1H, m), 6.84 - 6.90 (2H, m), 6.95 - 7.02 (2H, m).

Reference Example 185

Preparation of 1- [4- (tetrahydropyran-2-yloxy) phenyl] -4- (4-trifluoromethoxyphenyl) piperazine (an alternative method for synthesizing the compound in Reference Example 183) [1320] A mixture of 1- [4- (tetrahydropyran-2-yloxy) phenyl] piperazine (2.1 g, 8.05 mmol) prepared in Reference Example 184, 4-trifluoromethoxy-1-bromobenzene

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455/854 (1.9 g, 8.05 mmol), palladium acetate (72 mg, 0.32 mmol), BINAP (300 mg, 0.48 mmol) and sodium ter-butoxide (1.0 g, 10.5 mmol) in toluene (30 ml) was refluxed under an atmosphere of nitrogen for 5 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for some time. Insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 20/1) giving 1- [4- (tetrahydropyran-2-yloxy) phenyl ] -4- (4-fluoromethoxyphenyl) piperazine (3.1 g, 90% yield) as a white powder.

Reference Example 186

Preparation of 4- [4- (4-trifluoromethoxyphenyl) piperazin-1-yl] phenol [1321] A mixture of 1 - [4- (tetrahydropyran-2-yloxy) phenyl] -4- (4trifluoromethoxyphenyl) piperazine (2.65 g, 6.27 mmol) prepared in Reference Example 185 and pyridinium p-toluene sulfonate (473 mg, 1.88 mmol) in ethanol (50 ml) was stirred at 70 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and the saturated aqueous sodium hydrogen carbonate solution were added to the residue, which was stirred for some time. The mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) giving 4- [4- (4-trifluoromethoxyphenyl) piperazin-1 -yl] phenol (1.95 g, 92% yield) as a white powder.

[1322] ¹ H NMR (CDCb) δ ppm:

[1323] 3.19 - 3.24 (4H, m), 3.29 - 3.34 (4H, m), 4.50 (1H, s), 6.76 - 6.80 (2H, m) ,

6.87 - 6.97 (4H, m), 7.11 - 7.15 (2H, m).

[1324] Using corresponding starting materials, compounds of Reference Examples 187 and 188 were prepared in the same manner as described in Reference Example 186.

Reference Example 187

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456/854

4- [4- (4-trifluoromethylphenyl) piperazin-1-yl] phenol [1325] a white powder, 82% yield [1326] ¹ H NMR (CDCb) δ ppm:

[1327] 3.18 - 3.23 (4H, m), 3.41 - 3.45 (4H, m), 4.47 (1H, s), 6.76 - 6.82 (2H, m) ,

6.87 - 7.00 (4H, m), 7.48 - 7.52 (2H, m).

Reference Example 188

4- [4- (4-chlorophenyl) piperazin-1-yl] phenol [1328] a white powder, 23% yield [1329] ¹ H NMR (CDCb) δ ppm:

[1330] 3.18 - 3.23 (4H, m), 3.28 - 3.32 (4H, m), 4.45 (1H, s), 6.77 - 6.81 (2H, m) ,

6.87 - 6.92 (4H, m), 7.21 - 7.24 (2H, m).

Reference Example 189

Preparation of ter-butyl 4- (4-trifluoromethoxyphenoxy) pipendin-1-carboxylate [1331] tert-butyl 4-hydroxypiperidine-1-carboxylate (56.5 g, 0.28 mol), 4trifluoromethoxyphenol (50 g, 0 , 28 mol) and triphenylphosphine (108 g, 0.42 mol) were dissolved in THF (500 ml). Diethyl azodicarboxylate (65 ml, 0.42 mol) was added dropwise to this reflux solution, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 5/1) giving 4- (4-trifluoromethoxyphenoxy) pipendino-1- tert-butyl carboxylate (92 g, 91% yield) as a colorless oil.

[1332] ¹ H NMR (CDCb) δ ppm:

[1333] 1.47 (9H, s), 1.69 - 1.80 (2H, m), 1.85 - 1.96 (2H, m), 3.28 - 3.39 (2H, m) ,

3.64 - 3.75 (2H, m), 4.40 - 4.46 (1H, m), 6.85 - 6.92 (2H, m), 7.11 - 7.15 (2H, m ). Reference Example 190

Preparation of tert-butyl 4- (4-trifluoromethoxyphenoxy) pipendin [1334] 4- (4-trifluoromethoxyphenoxy) pipendin-1-carboxylate (92 g, 254.59 mmol) prepared in Reference Example 189 was dissolved in methylene chloride (100ml). Trifluoroacetic acid (200 ml) was added dropwise to this solution at room temperature, and the mixture was stirred overnight. THE

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457/854 reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride, which was neutralized with an aqueous solution of sodium hydroxide. The mixture was extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was then purified by column chromatography on silica gel (methylene chloride / methanol = 5/1) giving 4- (4trifluoromethoxyphenoxy) pipendin (55 g, 83% yield ) as a white powder. [1335] ¹ H NMR (CDCb) δ ppm:

[1336] 1.65 -1.78 (2H, m), 2.00 - 2.07 (2H, m), 2.73-2.83 (2H, m), 3.12 - 3.21 ( 2H,

m), 4.32-4.38 (2H, m), 6.85-6.92 (2H, m), 7.10 - 7.15 (2H, m).

Reference Example 191 [1337] Preparation of 1- [4- (tetrahydropyran-2-yloxy) phenyl] -4- (4-trifluoromethoxyphenoxy) piperidine [1338] A mixture of 4- (4-trifluoromethoxyphenoxy) piperidine (30,3 g, 0.116 mol) prepared in Reference Example 190, 2- (4-bromophenoxy) tetrahydropyran (30 g, 0.116 mol), palladium acetate (1.0 g, 4.64 mmol), BINAP (4.3 g, 6.96 mmol) and cesium carbonate (49 g, 0.151 mol) in toluene (300 ml) was refluxed under an atmosphere of nitrogen for 30 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for some time. Insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (nhexane / ethyl acetate = 20/1) giving 1 - [4- (tetrahydropyran-2-yloxy) phenyl] - 4- (4trifluoromethoxyphenoxy) piperidine (32.6 g, 64% yield) as a yellow powder.

[1339] ¹ H NMR (CDCb) δ ppm:

[1340] 1.55 -1.75 (3H, m), 1.81 - 2.20 (7H, m), 2.95 - 3.04 (2H, m), 3.38 - 3.42 ( 2H,

m), 3.55 - 3.66 (1H, m), 3.87 - 3.99 (1H, m), 4.36 - 4.45 (1H, m), 5.29 - 5.32 ( 1H, m), 6.89 - 7.01 (6H, m), 7.11 - 7.16 (2H, m).

Reference Example 192

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458/854

Preparation of 4- [4- (4-trifluoromethoxyphenoxy) pipendin-1-yl] phenol [1341] A mixture of 1 - [4- (tetrahydropyran-2-yloxy) phenyl] -4- (4trifluoromethoxyphenoxy) piperidine (30.1 g, 68.8 mmol) prepared in Reference Example 191 and pyridinium p-toluene sulfonate (5.2 g, 20.6 mmol) in ethanol (450 ml) was stirred at 70 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and the saturated aqueous sodium hydrogen carbonate solution were added to the residue, which was stirred for some time. The mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) giving 4- [4- (4-trifluoromethoxyphenoxy) pipendin-1 -yl] phenol (22.9 g, 94% yield) as a light brown powder.

[1342] ¹ H NMR (CDCb) δ ppm:

[1343] 1.88 - 2.02 (2H, m), 2.06 - 2.16 (2H, m), 2.92 - 3.02 (2H, m), 3.30 - 3.39 ( 2H,

m), 4.36-4.44 (1H, m), 4.74 (1H, s), 6.71 -6.78 (2H, m), 6.85-6.94 (4H, m) , 7.10 7.16 (2H, m).

Reference Example 193

Preparation of 4- [2-chloro-4- (tetrahydropyran-2-yloxy) phenyl] piperazine-1-carboxylate [1344] A mixture of ter-butyl piperazine-1-carboxylate (3.94 g, 21.6 mmol), 2- (4-bromo-3-chlorophenoxy) tetrahydropyran (5.61 g, 19.2 mol), palladium acetate (86, 4 mg, 0.39 mmol), BINAP (172 mg, 0.58 mmol) and sodium tert-butoxide (2.4 g, 25.0 mmol) in toluene (40 ml) was refluxed under an atmosphere of nitrogen for 2 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for some time. Insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 20/1) giving 4- [2-chloro-4- (tetrahydropyran-2-yloxy ) phenyl] ter-butyl piperazine-1-carboxylate (4.72 g,

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459/854 yield of 62%) as a yellow oil.

[1345] ¹ H NMR (CDCb) δ ppm:

[1346] 1.48 (9H, s), 1.51 - 2.04 (6H, m), 2.88 - 2.93 (4H, m), 3.56 - 3.63, (5H, m ),

3.83-3.94 (1H, m), 5.31 -5.34 (1H, m), 6.88-6.96 (2H, m), 7.10 - 7.13 (1H, m ). Reference Example 194

Preparation of tert-butyl 4- (2-chloro-4-hydroxyphenyl) piperazine-1-carboxylate [1347] A mixture of 4- [2-chloro-4- (tetrahydropyran-2-yloxy) phenyl] piperazine-1carboxylate tert-butyl (4.73 g, 11.9 mmol) prepared in Reference Example 193 and a catalytic amount of pyridinium p-toluene sulfonate in ethanol (50 ml) was stirred at 70 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue, which was stirred for some time. The resulting precipitates were collected by filtration, and dried in vacuo giving tert-butyl 4- (2-chloro-4-hydroxyphenyl) piperazine-1-carboxylate (2.68 g, 72% yield) as a white powder .

[1348] ¹ H NMR (CDCb) δ ppm:

[1349] 1.49 (9H, s), 2.87-2.91 (4H, m), 3.55 - 3.60 (4H, m), 5.19 (1H, br), 6.68 6.74 (1H, m), 6.88-6.93 (2H, m).

Reference Example 195

Preparation of tert-butyl 4- (4-acetoxybenzoyl) piperazine-1-carboxylate [1350] p-acetoxybenzoic acid (11 g, 61.1 mmol) was dissolved in methylene chloride (100 ml), to which DMF was added (3 drops) and thionyl chloride (5.54 ml, 76.3 mmol), and the mixture was heated to reflux for 2 hours. The mixture was cooled in an ice bath, to which was added a drip solution of tert-butyl piperazine-1-carboxylate (10.3 g, 55.5 mmol) and pyridine (12 ml, 0.15 mol) in chloride methylene (100 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride, and the mixture was washed with water, 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by means of chromatography

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460/854 column on silica gel (methylene chloride / ethyl acetate = 20/1) giving tert-butyl 4- (4acetoxybenzoyl) piperazine-1-carboxylate (18.5 g, 87% yield) as a colorless crystalline powder.

[1351] ¹ H NMR (CDCb) δ ppm:

[1352] 1.47 (9H, s), 2.31 (3H, s), 3.46 (8H, br), 7.12 - 7.18 (2H, m), 7.41 - 7.46 (2H,

m).

Reference Example 196

Preparation of tert-butyl 4- (4-hydroxybenzoyl) piperazine-1-carboxylate [1353] A mixture of tert-butyl 4- (4-acetoxybenzoyl) piperazine-1-carboxylate (18.5 g, 53.1 mmol ) prepared in Reference Example 195 and potassium carbonate (370 mg, 2.65 mmol) in methanol (200 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 5% hydrochloric acid and methylene chloride were added to the residue, and the mixture was stirred vigorously. The resulting precipitates were collected by filtration, washed with water and methylene chloride, and then dried in vacuo giving tert-butyl 4- (4hydroxybenzoyl) piperazine-1-carboxylate (14.9 g, 92% yield) like a white powder.

[1354] ¹ H NMR (CDCb) δ ppm:

[1355] 1.48 (9H, s), 3.46 (4H, br), 3.60 (4H, br), 6.75 - 6.79 (2H, m), 7.22 - 7.28 (2H, m).

Reference Example 197

Preparation of 1-benzyl-4- [4- (tetrahydropyran-2-yloxy) phenyl] piperidin-4-ol [1356] A solution of 2- (4-bromophenoxy) tetrahydropyran (7.2 g, 28 mmol) in THF (70 ml) was cooled to -60 ° C, to which was added dropwise a solution of n-butyl lithium (1.53 M) hexane (20 ml, 30.8 mmol), and the mixture was stirred for 30 minutes. Then a solution of 1-benzyl-4-piperidone (5.3 g, 28 mmol) in THF (20 ml) was added dropwise to this mixture, which was stirred for 3 hours while allowing it to reach a temperature of 0 ° C. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then

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461/854 filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 20/1) giving 1-benzyl-4- [4- (tetrahydropyran-2-yloxy) phenyl] piperidin-4- ol (5.27 g, 51% yield) as an orange oil.

[1357] ¹ H NMR (CDCb) δ ppm:

[1358] 1.52 - 2.21 (11H, m), 2.41 - 2.52 (2H, m), 2.74 - 2.78 (2H, m), 3.57 (2H, s) ,

3.56 - 3.63 (1H, m), 3.83 - 3.96 (1H, m), 5.39 - 5.42 (1H, m), 6.98 - 7.04 (2H, m ), 7.20 -7.44 (7H, m).

Reference Example 198

Preparation of tert-butyl 4- (4-hydroxyphenyl) piperidine-1-carboxylate [1359] A solution of 1-benzyl-4- [4- (tetrahydropyran-2-yloxy) phenyl] piperidin-4-ol (1, 67 g, 4.55 mmol) prepared in Reference Example 197 in acetonitrile (45 ml) was cooled to -10 ° C, to which was added triethylsilane (2.9 ml, 18.2 mmol) and boron trifluoride complex - diethyl ether (1.1 ml, 9.1 mmol), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (50 ml), to which a catalytic amount of 20% palladium hydroxide / carbon was added. The mixture was stirred at room temperature under atmospheric pressure of hydrogen overnight. The reaction mixture was filtered through Celite, di-tert-butyl dicarbonate (1.1 ml, 4.78 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving 4- (4-hydroxyphenyl) piperidine-1-carboxylate tert-butyl (1.07 g, 85% yield) as a colorless crystalline powder.

[1360] ¹ H NMR (CDCb) δ ppm:

[1361] 1.41 - 1.63 (2H, m), 1.49 (9H, s), 1.73 - 1.80 (2H, m), 2.50 - 2.62 (1H, m) ,

2.73-2.83 (2H, m), 4.19-4.24 (2H, m), 5.87 (1H, bs), 6.76-6.81 (2H, m), 7, 02-7.08 (2H, m).

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Reference Example 199

Preparation of tert-butyl 4- [3- (tetrahydropyran-2-yloxy) phenyl] piperazine-1-carboxylate [1362] A tert-butyl piperazine-1-carboxylate mixture (2.94 g, 15.8 mmol ), 2- (3-bromophenoxy) tetrahydropyran (3.69 g, 14.4 mmol), palladium acetate (64 mg, 0.29 mmol), BINAP (285 mg, 0.43 mmol) and tert-butoxide sodium (1.8 g, 18.7 mmol) in toluene (40 ml) was refluxed under an atmosphere of nitrogen for 2 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for some time. Insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 20/1) giving 4- [3 (tetrahydropyran-2-yloxy) phenyl] tert-butyl piperazine-1-carboxylate (5.3 g, 99% yield) as a colorless oil.

[1363] ¹ H NMR (CDCb) δ ppm:

[1364] 1.48 (9H, s), 1.52 -2.04 (6H, m), 3.10 - 3.15 (4H, m), 3.53 - 3.64 (5H, m) ,

3.87-3.94 (1H, m), 5.38-5.41 (1H, m), 6.53-6.63 (3H, m), 7.12 - 7.19 (1H, m ). Reference Example 200

Preparation of tert-butyl 4- (3-hydroxyphenyl) piperazine-1-carboxylate [1365] A mixture of tert-butyl 4- [3- (tetrahydropyran-2-yloxy) phenyl] piperazine-1-carboxylate (5, 20 g, 14.4 mmol) prepared in Reference Example 199 and a catalytic amount of pyridinium p-toluene sulfonate in ethanol (100 ml) was stirred at 70 ° C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue, which was stirred for some time. The resulting precipitates were collected by filtration, and then dried in vacuo giving tert-butyl 4- (3-hydroxyphenyl) piperazine-1-carboxylate (3.73 g, 93% yield) as a light brown powder.

[1366] ¹ H NMR (CDCb) δ ppm:

[1367] 1.49 (9H, s), 3.09 - 3.14 (4H, m), 3.54 - 3.59 (4H, m), 5.38 (1H, br), 6.33

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6.41 (2H, m), 6.47-6.52 (1H, m), 7.08-7.15 (1H, m).

Reference Example 201

Preparation of 3-methyl-2-methylene butylaldehyde [1368] 3-Methyl-2-methylene butylaldehyde was prepared according to the method described in the Journal of the American Chemical Society, 1957, p. 3267 (J. Am. Chem. Soc., 3267, 1957), that is, a mixture of isovaleraldehyde (100 ml, 932 mmol), 37% formalin (83.8 ml, 1120 mmol) and dimethylamine hydrochloride (91 , 2 g, 1120 mmol) was stirred at 70 ° C for 30 hours. The mixture was distilled with steam to separate the fraction, and the aqueous layer thus obtained was extracted with diethyl ether. The extracts were combined, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was distilled giving 3-methyl-2-methylene butylaldehyde (65.5 g, 72% yield) as a colorless oil.

[1369] boiling point: 105-115 ° C [1370] ¹ H NMR (CDCb) δ ppm:

[1371] 1.08 (6H, d, J = 6.9 Hz), 2.75 - 2.89 (1H, m), 5.95 (1H, s), 6.24 (1H, s), 9.53 (1H, s).

Reference Example 202

Preparation of 3-methyl-2-methylene-butan-1-ol [1372] A solution of 3-methyl-2-methylene butylaldehyde (65 g, 668 mmol) prepared in Reference Example 201 in THF (30 ml) was added by dripping to a suspension of lithium aluminum hydride (14.15 g, 373 mmol) in THF (1000 ml) while cooling in an ice bath, and the mixture was allowed to return to room temperature, and stirred for 2 hours. While cooling, water, 15% aqueous sodium hydroxide solution, and then water were added to the reaction mixture, which was filtered. The filtrate was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 3-methyl-2-methylenobutan-1-ol (61.5 g, 93% yield) as a colorless oil.

[1373] ¹ H NMR (CDCb) δ ppm:

[1374] 1.07 (6H, d, J = 6.9 Hz), 1.42 (1H, t, J = 6.1 Hz), 2.25-2.43 (1H, m), 4, 13 (2H, d, J = 6.1 Hz), 4.84 - 4.93 (1H, m), 4.98 - 5.05 (1H, m).

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Reference Example 203

Preparation of 2-methoxymethoxymethyl-3-methyl-1-butene [1375] Chloromethyl methyl ether (98 ml, 1292 mmol) and Netildiisopropylamine (234 ml, 1344 mmol) were added to a solution of 3-methyl-2-methylenebutane1 - ol (61.5 g, 615 mmol) prepared in Reference Example 202 in THF (500 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, and the mixture was washed with water and brine, dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 2-methoxymethoxymethyl-3-methyl-1-butene (89 g, quantitative) as a colorless oil.

[1376] ¹ H NMR (CDCb) δ ppm:

[1377] 1.07 (6H, d, J = 6.9 Hz), 2.25 - 2.41 (1H, m), 3.39 (3H, s), 4.05 (2H, s), 4.65 (2H, s), 4.87 - 4.95 (1H, m), 5.00 - 5.05 (1H, m).

Reference Example 204

Preparation of 2-methylenebutylaldehyde [1378] A mixture of butylaldehyde (100 ml, 1110 mmol), 37% formalin (99.8 ml, 1330 mmol) and dimethylamine chlorohydrate (108.6 g, 1330 mmol) was stirred at 70 ° C ° C for 23 hours. The mixture was distilled with steam to separate the fraction, and the aqueous layer thus obtained was extracted with diethyl ether. The extracts were combined, dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was distilled off giving 2-methylenebutylaldehyde (66.9 g, 72% yield) as a colorless oil.

[1379] boiling point: 70 - 93 ° C [1380] ¹ H NMR (CDCb) δ ppm:

[1381] 1.08 (3H, t, J = 7.5 Hz), 2.27 (2H, q, J = 7.5 Hz), 5.98 (1H, s), 6.25 (1H, s),

9.56 (1H, s).

Reference Example 205

Preparation of 2-methylene-1-butanol [1382] 2-Methylenebutylaldehyde (66.9 g, 796 mmol) prepared in Example

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Reference 204 was added by dripping to a suspension of lithium aluminum hydride (15.1 g, 398 mmol) in THF (1000 ml) while cooling in an ice bath, and the mixture was stirred for 1 hour. Water, 15% aqueous sodium hydroxide solution and then water were added to the reaction mixture, which was filtered, and the filtrate was dried over sodium sulfate. After filtration, and the filtrate was concentrated under reduced pressure giving 2-methylene-1-butanol (65.1 g, 95% yield) as a colorless oil.

[1383] ¹ H NMR (CDCb) δ ppm:

[1384] 1.07 (3H, t, J = 7.5 Hz), 1.44 (1H, t, J = 6.0 Hz), 2.13 (2H, q, J = 7.5 Hz) ,

4.09 (2H, d, J = 6.0 Hz), 4.82 - 4.93 (1H, m), 4.98 - 5.07 (1H, m).

Reference Example 206

Preparation of 2-methoxymethoxymethyl-1-butene [1385] Methyl chloromethyl ether (103.4 ml, 1363 mmol) and Netildiisopropylamine (247.2 ml, 1419 mmol) were added to a solution of 2-methylene-1-butanol (65.1 g, 757 mmol) prepared in Reference Example 205 in THF (750 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, and the mixture was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure giving 2-methoxymethoxymethyl-1-butene (98 g, quantitative) as a colorless oil.

[1386] ¹ H NMR (CDCb) δ ppm:

[1387] 1.07 (3H, t, J = 7.5 Hz), 2.09 (2H, q, J = 7.5 Hz), 3.38 (3H, s), 4.01 (2H, s),

4.64 (2H, s), 4.86 - 4.95 (1H, m), 5.00 - 5.05 (1H, m).

Reference Example 207

Preparation of terbutyl 4- [2-oxo-2- (4-oxopiperidin-1-yl) ethyl] piperazine-1-carboxylate [1388] 1- (2-chloroacetyl) piperidin-4-one (5.17 g, 29.4 mmol) was dissolved in acetonitrile (50 ml). To this solution were added tert-butyl piperazine-1-carboxylate (5.48 g, 29.4 mmol) and N-ethylldiisopropylamine (6.2 ml, 35.3 mmol), and the mixture was

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466/854 heated to reflux for 2 hours. The reaction mixture was allowed to return to room temperature, to which water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 4- [2-oxo-2- (4-oxopiperidin-1 -yl) ethyl] ter-butyl piperazine-1-carboxylate (6.49 g, 68% yield) as a light yellow crystalline powder.

[1389] ¹ H NMR (CDCb) δ ppm:

[1390] 1.46 (9H, s), 2.44 - 2.54 (8H, m), 3.28 (2H, s), 3.42 - 3.47 (4H, m), 3.85 3.90 (4H, m).

Reference Example 208

Preparation of 4-methyl-4-pentenyl acetate [1391] Potassium tert-butoxide (9.4 g, 84 mmol) was added to a mixture of methyltriphenylphosphonium bromide (30 g, 84 mmol) in THF (300 ml ), and the mixture was stirred at room temperature for 40 minutes. To the mixture, a solution of 4-oxopentyl acetate (9.9 g, 68.8 mmol) in THF (30 ml) was gradually added dropwise while cooling in an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with diethyl ether twice. The extracts were combined, washed with brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 4/1) giving 4-methyl-4-pentenyl acetate (5.9 g, 60.4% yield) like a colorless oil.

[1392] ¹ H NMR (CDCb) δ ppm:

[1393] 1.70 - 1.86 (5H, m), 2.00-2.14 (5H, m), 4.07 (2H, t, J = 6.7 Hz), 4.69 (1H ,

s), 4.74 (1H, s).

Reference Example 209

Preparation of benzyl 4- (2-methyl-2-oxiranylmethyl) piperazine-1-carboxylate [1394] Trimethylsulfoxonium iodide (1.96 g, 8.91 mmol) was added to a

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467/854 sodium hydride suspension (0.37 g, 9.32 mmol) in DMSO (20 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 30 minutes. To the mixture, a solution of benzyl 4- (2-oxopropyl) piperazine-1-carboxylate (2.24 g, 8.10 mmol) in DMSO (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure giving benzyl 4- (2-methyl2-oxiranylmethyl) piperazine-1-carboxylate (1.51 g, 64% yield) as a light yellow oil.

[1395] ¹ H NMR (CDCb) δ ppm:

[1396] 1.37 (3H, s), 2.27 - 2.63 (8H, m), 3.44 - 3.63 (4H, m), 5.13 (2H, s), 7.29 7.44 (5H, m).

Reference Example 210

Preparation of tert-butyl 4- (2-methyl-2-oxiranylmethyl) homopiperazine-1-carboxylate [1397] Trimethylsulfoxonium iodide (22.95 g, 104 mmol) was gradually added to a sodium hydride suspension (4 , 3 g, 109 mmol) in DMSO (200 ml), and the mixture was stirred at room temperature for 2 hours. To this was added gradually a solution of tert-butyl 4- (2-oxopropyl) homopiperazine-1-carboxylate (24.3 g, 94.8 mmol) prepared in Reference Example 10 in DMSO (25 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 4 (2-methyl-2-oxiranylmethyl) homopiperazine-1-carboxylate (15.38 g , 60% yield) as a light yellow oil.

[1398] ¹ H NMR (CDCb) δ ppm:

[1399] 1.38 (3H, s), 1.43 (9H, s), 1.69 - 1.90 (2H, m), 2.40 - 2.75 (8H, m), 3.36 3.55 (4H, m).

Reference Example 211

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Preparation of tert-butyl 4- [2- (2-methyl-2-oxiranyl) ethyl] piperazine-1-carboxylate [1400] Trimethylsulfoxonium iodide (7.8 g, 35 mmol) was gradually added to a suspension of sodium hydride (1.2 g, 35 mmol) in DMSO (120 ml), under an atmosphere of nitrogen, and the mixture was stirred at room temperature for 2 hours. To this was added gradually a solution of tert-butyl 4- (3oxobutyl) piperazine-1-carboxylate (6.1 g, 23.8 mmol) in DMSO (10 ml), and the mixture was stirred at room temperature. room for 1.5 hours, and then at 50 to 60 ° C for 1.5 hours. The reaction solution was allowed to return to room temperature, poured into ice water, and extracted with ethyl acetate three times. The extracts were combined, washed with water three times and then washed with a saturated saline solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving tert-butyl 4- [2- (2-methyl-2oxyranyl) ethyl] piperazine-1-carboxylate (5.6 g, 87%) as a light yellow oil.

[1401] ¹ H NMR (CDCb) δ ppm:

[1402] 1.33 (3H, s), 1.46 (9H, s), 1.66 - 1.85 (2H, m), 2.28 - 2.50 (6H, m), 2.55 2.66 (2H, m), 3.34 - 3.47 (4H, m).

Reference Example 212

Preparation of 1 - (2-methyl-2-oxiranylmethyl) -4- (4-trifluoromethylphenyl) piperazine [1403] Trimethylsulfoxonium iodide (2.5 g, 11.6 mmol) was gradually added to a suspension of sodium hydride (484 mg, 12.1 mmol) in dimethylsulfoxide (30 ml), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 1- {4- (4-trifluoromethylphenyl) piperazin-1-yl} propan-2-one (3.4 g, 11.9 mmol) in dimethyl sulfoxide (20 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 1 - (2-methyl-2-oxiranylmethyl) 4- (4-trifluoromethylphenyl) piperazine (3.2 g, 98% yield) as a yellow powder

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[1404] ¹ H NMR (CDCb) δ ppm:

[1405] 1.40 (3H, s), 2.33 (1H, d, J = 13.0 Hz), 2.53 - 2.73 (7H, m), 3.26 - 3.30 (4H ,

m), 6.91 (2H, d, J = 8.7 Hz), 7.47 (2H, d, J = 8.7 Hz).

[1406] Compounds of Reference Examples 213 to 217 were prepared in the same manner as described in Reference Example 212.

Reference Example 213

1- (2-methyl-2-oxiranylmethyl) -4- (4-biphenylyl) piperazine [1407] a light yellow powder, 99% yield [1408] ¹ H NMR (CDCb) δ ppm:

[1409] 1.41 (3H, s), 2.37 (1H, d, J = 12.9 Hz), 2.58 - 2.76 (7H, m), 3.23 - 3.28 (4H ,

m), 6.97 - 7.01 (2H, m), 7.24 - 7.30 (1H, m), 7.37 - 7.43 (2H, m), 7.49 - 7.58 ( 4H, m).

Reference Example 214

1- (2-methyl-2-oxiranylmethyl) -4- (4-chlorophenyl) piperazine [1410] a light yellow powder, 99% yield [1411] ¹ H NMR (CDCb) δ ppm:

[1412] 1.39 (3H, s), 2.34 (1H, d, J = 12.9 Hz), 2.54-2.73 (7H, m), 3.14-3.18 (4H ,

m), 6.81 - 6.87 (2H, m), 7.16 - 7.22 (2H, m).

Reference Example 215

1- (2-methyl-2-oxiranylmethyl) -4- (4-trifluoromethoxyphenyl) piperazine [1413] a light yellow powder, 99% yield [1414] ¹ H NMR (CDCb) δ ppm:

[1415] 1.40 (3H, s), 2.34 (1H, d, J = 12.9 Hz), 2.54-2.73 (7H, m), 3.16-3.20 (4H ,

m), 6.85 - 6.92 (2H, m), 7.08 - 7.13 (2H, m).

Reference Example 216

1- (2-methyl-2-oxiranylmethyl) -4- (pyridine-2-yl) piperazine [1416] a light yellow powder, 99% yield [1417] ¹ H NMR (CDCb) δ ppm:

[1418] 1.41 (3H, s), 2.35 (1H, d, J = 12.9 Hz), 2.50 - 2.69 (7H, m), 3.48 - 3.60 (4H ,

m), 6.59-6.66 (2H, m), 7.43 - 7.50 (1H, m), 8.17 - 8.20 (1H, m).

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Reference Example 217

- (2-methyl-2-oxiranylmethyl) -4- (pyrimidin-2-yl) piperazine [1419] a light yellow powder, 99% yield [1420] ¹ H NMR (CDCb) δ ppm:

[1421] 1.41 (3H, s), 2.36 (1H, d, J = 12.9 Hz), 2.45 - 2.64 (7H, m), 3.81 - 3.85 (4H ,

m), 6.47 (1H, t, J = 4.8 Hz), 8.30 (2H, d, J = 4.8 Hz).

Reference Example 218

Preparation of N-methyl- [1- (2-methyl-2-oxiranylmethyl) piperidin-4-yl] tert-butyl carbamate [1422] Trimethylsulfoxonium iodide (1.96 g, 8.89 mmol) was gradually added to a suspension of sodium hydride (372 mg, 9.32 mmol) in dimethyl sulfoxide (20 ml), and the mixture was stirred at room temperature for 1.5 hours. To this was added a solution of tert-butyl N-methyl- [1- (2-oxopropyl) piperidin-4-yl] carbamate (2.3 g, 8.5 mmol) in dimethyl sulfoxide (20 ml), and the mixture it was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with a saturated saline solution, dried over magnesium sulfate, and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving N-methyl- [1- (2-methyl-2oxyranylmethyl) ) ter-butyl piperidin-4-yl] carbamate (2.1 g, 86% yield) as a light yellow oily material.

[1423] ¹ H NMR (CDCb) δ ppm:

[1424] 1.36 (3H, s), 1.46 (9H, s), 1.55 -1.79 (5H, m), 1.97 - 2.13 (2H, m), 2.30 (1H, d, J = 12.9 Hz), 2.49 (1H, d, J = 12.9 Hz), 2.59 (2H, s), 2.74 (3H, s), 2.88 - 3.06 (2H, m).

Reference Example 219

Preparation of 3- (2-methyl-2-oxiranyl) -pyridine [1425] Using 3-acetylpyridine (8 g, 66.1 mmol), a brown heat oil of 3- (2-methyl-2-oxiranyl) was produced ) pyridine (7 g, 78.4% yield) in the same manner as in Reference Example 218.

[1426] ¹ H NMR (CDCb) δ ppm:

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Preparation of tert-butyl 1-oxa-6-azospiro [2.5] octane-6-carboxylate [1428] Trimethylsulfoxonium iodide (70 g, 0.32 mol) was gradually added to a sodium hydride suspension ( 13.3 g, 0.33 mol) in dimethyl sulfoxide (600 ml), and the mixture was stirred at room temperature for 1 hour. To this was added tert-butyl 4oxo-piperidine-1-carboxylate (58 g, 0.291 mol), and the mixture was stirred at 55 ° C for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was crystallized from n-hexane giving tert-butyl 1-oxa-6-azospiro [2.5] octane-6-carboxylate (61.7 g, yield 96 %) as a white powder.

[1429] ¹ H NMR (CDCb) δ ppm:

[1430] 1.40 - 1.53 (2H, m), 1.47 (9H, s), 1.72 - 1.85 (2H, m), 2.69 (2H, s), 3.37 -

3.48 (2H, m), 3.67 - 3.77 (2H, m).

Reference Example 221

Preparation of tert-butyl 4- [2- (1-oxa-6-azaospiro [2.5] octan-6-yl) -2-oxoethyl] piperazine-1 carboxylate [1431] Trimethylsulfoxonium iodide ( 2.02 g, 9.20 mmol) to a suspension of sodium hydride (385 mg, 9.64 mmol) in dimethyl sulfoxide (50 ml), and the resulting mixture was stirred at room temperature for 1 hour. To this was added 4- [2-oxo-2- (4-oxopiperidin-1-yl) ethyl] piperazine-1-carboxylate (2.85 g, 8.76 mmol) in DMSO (10 ml ), and the mixture was stirred at room temperature for 2 hours, and stirred at 55 ° C for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure to give ter-butyl 4- [2- (1-oxa-6azaospiro [2.5] octan-6-yl) -2-oxoethyl] piperazine-1-carboxylate (2.97 g,

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472/854 yield 99%) as a white solid.

[1432] ¹ H NMR (CDCb) δ ppm:

[1433] 1.45 - 1.54 (1H, m), 1.48 (9H, s), 1.78 - 1.93 (1H, m), 2.44 - 2.49 (4H, m) ,

2.62 (2H, s), 2.73 (2H, s), 3.42 - 3.47 (2H, m), 3.52 - 3.68 (1H, m), 3.77 - 3, 88 (1H, m). Reference Example 222

Preparation of 6- (4-trifluoromethylphenyl) -1-oxa-6-azospiro [2.5] octane [1434] Trimethylsulfoxonium iodide (2.00 g, 9.02 mmol) was gradually added to a suspension of hydride sodium (361 mg, 9.02 mmol) in dimethyl sulfoxide (30 ml), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 1- (4-trifluoromethylphenyl) pipendin-4-one (2.00 g, 8.2 mmol) in DMSO (10 ml), and the mixture was stirred overnight. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and then filtered. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 5/1) giving 6- (4-trifluoromethylphenyl) -1-oxa-6-azospiro [2.5] octane ( 1.51 g, 72% yield) as a light yellow crystalline powder.

[1435] ¹ H NMR (CDCb) δ ppm:

[1436] 1.54 - 1.65 (2H, m), 1.91 - 2.04 (2H, m), 2.54 - 2.59 (2H, m), 2.73 (2H, s) ,

3.38 - 3.48 (1H, m), 3.52 - 3.62 (1H, m), 6.95 (2H, d, J = 8.7 Hz), 7.48 (2H, d, J = 8.7 Hz).

Reference Example 223

Preparation of 3- (2-methyl-2-oxiranyl) propyl acetate [1437] M-chloroperbenzoic acid (12.3 g, 71.30 mmol) was gradually added to a solution of 4-methyl-4- acetate pentenyl (5.9 g, 41.5 mmol) prepared in Reference Example 208 in methylene chloride (60 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium sulfite solution and saturated aqueous sodium carbonate solution were added to the mixture while cooling in an ice bath, which was stirred for 30 minutes, and the organic layer was separated. The aqueous layer was extracted with methylene chloride. The extracts were combined, washed with

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473/854 saturated aqueous solution of sodium bicarbonate and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 3- (2-methyl-2-oxiranyl) propyl acetate (6.9 g, quantitative) as a colorless oil.

[1438] ¹ H NMR (CDCb) δ ppm:

[1439] 1.33 (3H, s), 1.56-1.79 (4H, m), 2.05 (3H, s), 2.56 - 2.70 (2H, m), 4.08 (2H, t, J = 6.5 Hz).

Reference Example 224

Preparation of 1-ethyl-5- [2- (2-methyl-2-oxiranyl) ethyl] -1 H-tetrazole [1440] M-chloroperbenzoic acid (1.97 g, 7.99 mmol) was gradually added to a solution of 1-ethyl-5- (3-methyl-3-butenyl) -1 H-tetrazole (0.95 g, 5.71 mmol) in methylene chloride (20 ml) while cooling in an ice bath , and the mixture was stirred at room temperature for 21 hours. Aqueous sodium thiosulfate solution and aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the resulting mixture was filtered. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 1-ethyl-5- [2- (2-methyl-2-oxiranyl) ethyl] -1 H-tetrazole (1.2 g, quantitative) as a light yellow oil.

[1441] ¹ H NMR (CDCb) δ ppm:

[1442] 1.40 (3H, s), 1.55 (3H, t, J = 7.3 Hz), 2.00-2.16 (1H, m), 2.20 -2.37 (1H ,

m), 2.66 (2H, s), 2.78 - 2.98 (2H, m), 4.32 (2H, q, J = 7.3 Hz).

[1443] Using corresponding starting materials, compounds of Reference Examples 225 and 226 were prepared in the same manner as described in Reference Example 224.

Reference Example 225

-phen l-5- [2- (2-methyl l-2-oxiranyl) ethyl] -1 H-tetrazole [1444] 100% yield [1445] ¹ H NMR (CDCb) δ ppm:

[1446] 1.32 (3H, s), 2.01 - 2.28 (2H, m), 2.59 (2H, s), 2.92 - 2.99 (2H, m), 7.43 7.47 (2H, m), 7.58 - 7.63 (3H, m).

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Reference Example 226

- (4-chlorophenyl) -5- [2- (2-m ethyl 1-2-oxiranyl) ethyl] -1 H-tetrazole [1447] 100% yield [1448] ¹ H NMR (CDCb) δ ppm:

[1449] 1.33 (3H, s), 2.00 - 2.12 (1H, m), 2.19 - 2.31 (1H, m), 2.60 (2H, s), 2.90 -

2.97 (2H, m), 7.39 - 7.45 (2H, m), 7.56 - 7.62 (2H, m).

Reference Example 227

Preparation of 1- (2-methyl-2-oxiranylmethyl) -1,4-dihydrobenzo [d] [1,3] oxazin-2-one [1450] M-chloroperbenzoic acid (13.76 g, 55, 81 mmol) to a solution of 1- (2-methyl-2-propenyl) -1,4-dihydrobenzo [d] [1,3] oxazin-2-one (7.09 g, 34.88 mmol) in chloride methylene (150 ml), and the mixture was stirred at room temperature for 24 hours. Aqueous sodium thiosulfate solution and aqueous sodium hydrogen carbonate solution were added to the mixture, and the resulting mixture was filtered. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 4/1) giving 1- (2-methyl-2-oxiranylmethyl) -1,4 dihydrobenzo [d] [1,3 ] oxazin-2-one (5.13 g, 67%) as a light yellow oil.

[1451] ¹ H NMR (CDCb) δ ppm:

[1452] 1.39 (3H, s), 2.70 (1H, d, J = 4.4 Hz), 2.78 (1H, d, J = 4.4 Hz), 3.79 (1H, d,

J = 15.5 Hz), 4.51 (1H, d, J = 15.5 Hz), 5.23 (2H, s), 7.04 - 7.13 (2H, m), 7.21 - 7.27 (1H, m), 7.29-7.38 (1H, m).

Reference Example 228

Preparation of 3- (2-methyl-2-oxiranylmethyl) -3H-benzoxazol-2-one [1453] M-chloroperbenzoic acid (1.66 g, 9.65 mmol) was added to a mixture of 3- (2 -methyl-2-propenyl) -3H-benzoxazol-2-one (1.66 g, 8.77 mmol) in methylene chloride (30 ml) while cooling in an ice bath, and the mixture was stirred at temperature overnight. The reaction mixture was filtered, and the filtrate was washed with a 20% aqueous sodium sulfite solution, saturated aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate.

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After filtration, the filtrate was concentrated under reduced pressure. The residue was treated with methylene chloride / n-hexane, and the resulting precipitates were collected by filtration giving 3- (2-methyl-2-oxiranylmethyl) -3H-benzoxazol-2-one (1.78 g, yield 99%) as a white powder.

[1454] ¹ H NMR (CDCb) δ ppm:

[1455] 1.38 (3H, s), 2.73 (1H, d, J = 4.3 Hz), 2.81 (1H, d, J = 4.3 Hz), 3.68 (1H, d,

J = 15.0 Hz), 4.26 (1H, d, J = 15.0 Hz), 7.09-7.29 (4H, m).

[1456] Using corresponding starting materials, compounds of Reference Examples 229 to 232 were prepared in the same manner as described in Reference Example 228.

Reference Example 229 5-chloro-3- (2-methyl-2-oxiranylmethyl) -3H-benzoxazol-2-one [1457] 93% yield [1458] ¹ H NMR (CDCb) δ ppm:

[1459] 1.38 (3H, s), 2.75 (1H, d, J = 4.2 Hz), 2.79 (1H, d, J = 4.2 Hz), 3.60 (1H, d,

J = 15.1 Hz), 4.28 (1H, d, J = 15.1 Hz), 7.05 - 7.16 (2H, m), 7.20 - 7.27 (1H, m). Reference Example 230 5-fluoro-3- (2-methyl-2-oxiranylmethyl) -3H-benzoxazol-2-one [1460] 97% yield [1461] ¹ H NMR (CDCb) δ ppm:

[1462] 1.38 (3H, s), 2.75 (1H, d, J = 4.3 Hz), 2.80 (1H, d, J = 4.3 Hz), 3.60 (1H, d,

J = 15.1 Hz), 4.29 (1H, d, J = 15.1 Hz), 6.75-6.85 (1H, m), 7.01 (1H, dd, J = 2.6 Hz, 7.9 Hz), 7.13 (1H, dd, J = 4.2 Hz, 8.8 Hz).

Reference Example 231 5-phenyl-3- (2-methyl-2-oxiranylmethyl) -3H-benzoxazol-2-one [1463] 92% yield [1464] ¹ H NMR (CDCb) δ ppm:

[1465] 1.40 (3H, s), 2.74 (1H, d, J = 4.3 Hz), 2.82 (1H, d, J = 4.3 Hz), 3.70 (1H, d,

J = 15.0 Hz), 4.32 (1H, d, J = 15.0 Hz), 7.25 (1H, d, J = 8.4 Hz), 7.29 - 7.49 (5H, m), 7.57 (2H, dd, J = 1.6 Hz, 8.5 Hz).

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Reference Example 232

5-bromo-3- (2-methyl-2-oxiranylmethyl) -3H-benzoxazol-2-one [1466] 80% yield [1467] ¹ H NMR (CDCb) δ ppm:

[1468] 1.38 (3H, s), 2.75 (1H, d, J = 4.2 Hz), 2.79 (1H, d, J = 4.2 Hz), 3.61 (1H, d,

J = 15.1 Hz), 4.27 (1H, d, J = 15.1 Hz), 7.08 (1H, d, J = 8.5 Hz), 7.18 - 7.31 (1H, m),

7.38 (1H, d, J = 1.9 Hz).

Reference Example 233

Preparation of 1 - (2-methyl-2-oxiranylmethyl) -3-phenyl-1,3-dihydrobenzimidazole-2-one [1469] Using 1- (2-methyl-2-propenyl) -3-phenyl-1,3 -dihydrobenzimidazole-2-one (720 mg, 2.72 mmol), 1- (2-methyl-2-oxiranylmethyl) -3-phenyl-1,3-dihydrobenzimidazole2-one (758 mg, 99% yield was prepared ) as a light yellow oil in the same manner as described in Reference Example 228.

[1470] ¹ H NMR (CDCb) δ ppm:

[1471] 1.40 (3H, s), 2.73 (1H, d, J = 4.5 Hz), 2.86 (1H, d, J = 4.5 Hz), 3.82 (1H, d,

J = 15.0 Hz), 4.38 (1H, d, J = 15.0 Hz), 7.02 - 7.30 (4H, m), 7.34 - 7.45 (1H, m), 7.50 7.57 (4H, m).

[1472] Using corresponding starting materials, compounds of Reference Examples 234 to 245 were prepared in the same manner as described in Reference Example 233.

Reference Example 234

1- (4-fluorophenyl) -3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1473] 96% yield [1474] ¹ H NMR (CDCb) δ ppm:

[1475] 1.40 (3H, s), 2.73 (1H, d, J = 4.5 Hz), 2.85 (1H, d, J = 4.5 Hz), 3.81 (1H, d,

J = 15.0 Hz), 4.38 (1H, d, J = 15.0 Hz), 7.00 - 7.30 (6H, m), 7.43 - 7.57 (2H, m). Reference Example 235

- (1-ter-butoxycarbonylpiperidin-4-yl) -3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-

2- one [1476] 40% yield

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477/854 [1477] ¹ H NMR (CDCb) δ ppm:

[1478] 1.34 (3H, s), 1.54 (9H, s), 1.71-1.87 (2H, m), 2.20 - 2.42 (2H, m), 2.70 (1H, d, J = 4.5 Hz), 2.71 -2.89 (3H, m), 3.75 (1H, d, J = 15.0 Hz), 4.20-4.53 ( 4H, m), 7.00 - 7.13 (3H, m), 7.15 - 7.25 (1H, m).

Reference Example 236

1-methyl-3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1479] 68% yield [1480] ¹ H NMR (CDCb) δ ppm:

[1481] 1.34 (3H, s), 2.69 (1H, d, J = 4.5 Hz), 2.78 (1H, d, J = 4.5 Hz), 3.44 (3H, s),

3.76 (1H, d, J = 15.0 Hz), 4.31 (1H, d, J = 15.0 Hz), 6.91 - 7.00 (1H, m), 7.05 - 5 , 25 (3H, m).

Reference Example 237

5- chloro-1-methyl-3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1482] 89% yield [1483] ¹ H NMR (CDCb) δ ppm:

[1484] 1.34 (3H, s), 2.70 (1H, d, J = 4.4 Hz), 2.76 (1H, d, J = 4.4 Hz), 3.42 (3H, s),

3.69 (1H, d, J = 15.1 Hz), 4.28 (1H, d, J = 15.1 Hz), 6.88 (1H, d, J = 8.3 Hz), 7, 09 (1H, dd, J = 1.9 Hz, 8.3 Hz), 7.22 (1H, d, J = 1.9 Hz).

Reference Example 238

-methyl-3- (2-methyl-2-oxiranylmethyl) -5-trifluoromethyl-1,3-dihydrobenzimidazole-2-one [1485] 99% yield [1486] ¹ H NMR (CDCb) δ ppm:

[1487] 1.36 (3H, s), 2.71 (1H, d, J = 4.4 Hz), 2.77 (1H, d, J = 4.4 Hz), 3.47 (3H, s),

3.74 (1H, d, J = 15.1 Hz), 4.38 (1H, d, J = 15.1 Hz), 7.04 (1H, d, J = 8.2 Hz), 7, 39 (1H, dd, J = 1.9 Hz, 8.2 Hz), 7.45 (1H, d, J = 1.9 Hz).

Reference Example 239

6- chloro-1-methyl-3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1488] 99% yield [1489] ¹ H NMR (CDCb) δ ppm:

[1490] 1.32 (3H, s), 2.69 (1H, d, J = 4.6 Hz), 2.75 (1H, d, J = 4.6 Hz), 3.41 (3H, s),

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3.68 (1H, d, J = 15.1 Hz), 4.33 (1H, d, J = 15.1 Hz), 6.97 (1H, d, J = 1.9 Hz), 7, 07 (1H, dd, J = 1.9 Hz, 8.4 Hz), 7.13 (1H, d, J = 8.4 Hz).

Reference Example 240

5-fluoro-1-methyl-3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1491] 66% yield [1492] ¹ H NMR (CDCb) δ ppm:

[1493] 1.34 (3H, s), 2.70 (1H, d, J = 4.4 Hz), 2.77 (1H, d, J = 4.4 Hz), 3.42 (3H, s),

3.77 (1H, d, J = 15.0 Hz), 4.33 (1H, d, J = 15.0 Hz), 6.74-6.91 (2H, m), 7.00 (1H , dd, J = 2.2 Hz, 8.6 Hz).

Reference Example 241

5-chloro-1-ethyl-3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1494] 100% yield [1495] ¹ H NMR (CDCb) δ ppm:

[1496] 1.25 - 1.39 (6H, m), 2.70 (1H, d, J = 4.4 Hz), 2.76 (1H, d, J = 4.4 Hz), 3, 69 (1H, d, J = 15.1 Hz), 3.93 (2H, q, J = 7.3 Hz), 4.30 (1H, d, J = 15.1 Hz), 6.90 ( 1H, d, J = 8.3 Hz), 7.07 (1H, dd, J = 2.0 Hz, 8.3 Hz), 7.23 (1H, d, J = 2.0 Hz).

Reference Example 242

5-chloro-1-isopropyl-3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1497] 100% yield [1498] ¹ H NMR (CDCb) δ ppm:

[1499] 1.34 (3H, s), 1.53 (6H, dd, J = 2.1 Hz, 6.7 Hz), 2.70 (1H, d, J = 4.5 Hz), 2 , 75 (1H, d, J = 4.5 Hz), 3.68 (1H, d, J = 15.1 Hz), 4.28 (1H, d, J = 15.1 Hz), 4.65 - 4.79 (1H, m), 7.04 (2H, s), 7.22 (1H, s).

Reference Example 243

5-dimethylamino-1-methyl-3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1500] 100% yield [1501] ¹ H NMR (DMSO-de) δ ppm:

[1502] 1.33 (3H, s), 2.69 (1H, d, J = 4.5 Hz), 2.79 (1H, d, J = 4.5 Hz), 2.92 (6H, s),

3.39 (3H, s), 3.67 (1H, d, J = 15.0 Hz), 4.32 (1H, d, J = 15.0 Hz), 6.55 (1H, dd, J = 2.4 Hz, 8.6 Hz), 6.71 (1H, d, J = 2.4 Hz), 6.85 (1H, d, J = 8.6 Hz).

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Reference Example 244

5-chloro-1- (n-hexyl) -3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1503] 100% yield [1504] ¹ H NMR (CDCb) δ ppm:

[1505] 0.87 (3H, t, J = 6.9 Hz), 1.18 - 1.43 (9H, m), 1.64 - 1.80 (2H, m), 2.70 (1H , d, J = 4.4 Hz), 2.75 (1H, d, J = 4.4 Hz), 3.69 (1H, d, J = 15.0 Hz), 3.86 (2H, t , J = 7.4

Hz), 4.30 (1H, d, J = 15.0 Hz), 6.88 (1H, d, J = 8.4 Hz), 7.06 (1H, dd, J = 1.9 Hz, 8.4 Hz), 7.22 (1H, d, J = 1.9 Hz).

Reference Example 245

5-ethoxycarbonyl-1-methyl-3- (2-methyl-2-oxiranylmethyl) -1,3-dihydrobenzimidazole-2-one [1506] 100% yield [1507] ¹ H NMR (CDCb) δ ppm:

[1508] 1.32 - 1.43 (6H, m), 2.69 (1H, d, J = 4.5 Hz), 2.78 (1H, d, J = 4.5 Hz), 3, 47 (3H, s), 3.87 (1H, d, J = 15.0 Hz), 4.28 (1H, d, J = 15.0 Hz), 4.39 (2H, q, J = 7 , 2 Hz), 7.00 (1H, d, J = 8.2 Hz), 7.85 (1H, d, J = 1.5 Hz), 7.90 (1H, dd, J = 1.5 Hz, 8.2 Hz). Reference Example 246

Preparation of 1-benzyl-3- (2-methyl-2-oxiranylmethyl) imidazolidin-2-one [1509] Using 1-benzyl-3- (2-methyl-2-propenyl) imidazolidin-2-one ( 1.63 g, 7.05 mmol), 1-benzyl-3- (2-methyl-2-oxiranylmethyl) imidazolidin-2-one (680 mg, 39% yield) as a light yellow oil in the same manner as described in Reference Example 228.

[1510] ¹ H NMR (CDCb) δ ppm:

[1511] 1.35 (3H, s), 2.62 (1H, d, J = 4.7 Hz), 2.69 (1H, d, J = 4.7 Hz), 3.05 - 3, 25 (3H, m), 3.27 - 3.49 (2H, m), 3.61 (1H, d, J = 14.6 Hz), 4.39 (2H, s), 7.20 - 7 , 34 (5H, m).

[1512] Using corresponding starting materials, compounds of Reference Examples 247 to 250 were prepared in the same manner as described in Reference Example 246.

Reference Example 247

1- (2-methyl-2-oxiranylmethyl) -3-phenylimidazolidin-2-one

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480/854 [1513] yield from 58% [1514] ¹ H NMR (CDCb) δ ppm:

[1515] 1.37 (3H, s), 2.65 (1H, d, J = 4.6 Hz), 2.72 (1H, d, J = 4.6 Hz), 3.18 (1H, d,

J = 14.7 Hz), 3.48 - 3.61 (2H, m), 3.64 (1H, d, J = 14.7 Hz), 3.77 - 3.91 (2H, m), 7.03 (1H, t, J = 7.3 Hz), 7.25 - 7.36 (2H, m), 7.56 (2H, d, J = 7.9 Hz).

Reference Example 248 1- (4-fluorobenzyl) -3- (2-methyl-2-oxiranylmethyl) imidazolidin-2-one [1516] 34% yield [1517] ¹ H NMR (CDCb) δ ppm:

[1518] 1.35 (3H, s), 2.62 (1H, d, J = 4.7 Hz), 2.68 (1H, d, J = 4.7 Hz), 3.12 (1H, d,

J = 14.6 Hz), 3.16 - 3.20 (2H, m), 3.27 - 3.45 (2H, m), 3.61 (1H, d, J = 14.6 Hz), 4.35 (2H, s), 6.89 - 7.07 (2H, m), 7.14 - 7.27 (2H, m).

Reference Example 249 1- (4-bromobenzyl) -3- (2-methyl-2-oxiranylmethyl) imidazolidin-2-one [1519] 51% yield [1520] ¹ H NMR (CDCb) δ ppm:

[1521] 1.34 (3H, s), 2.62 (1H, d, J = 4.7 Hz), 2.67 (1H, d, J = 4.7 Hz), 3.12 (1H, d,

J = 14.7 Hz), 3.16 - 3.25 (2H, m), 3.27 - 3.50 (2H, m), 3.61 (1H, d, J = 14.7 Hz), 4.33 (2H, s), 7.15 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz).

Reference Example 250 1- (4-methoxybenzyl) -3- (2-methyl-2-oxiranylmethyl) imidazolidin-2-one [1522] 43% yield [1523] ¹ H NMR (CDCb) δ ppm:

[1524] 1.34 (3H, s), 2.61 (1H, d, J = 4.7 Hz), 2.67 (1H, d, J = 4.7 Hz), 3.07 - 3, 23 (3H, m), 3.27 - 3.50 (2H, m), 3.58 (1H, d, J = 14.6 Hz), 3.80 (3H, s), 4.32 (2H , s), 6.86 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz).

Reference Example 251 1- (4-chlorobenzyl) -3- (2-methyl-2-oxiranylmethyl) imidazolidin-2-one [1525] Sodium hydride (99 mg, 2.49 mmol) was added to a solution of 2-methyl-2-oxiranylmethyl toluene-4-sulfonate (500 mg, 2.37 mmol) in DMF (5 ml)

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481/854 while cooling in an ice bath, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 1- (4chlorobenzyl) imidazolidin-2-one (633 mg, 2.61 mmol) in DMF (5 ml) while cooling in an ice bath, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether twice. The extracts were combined, washed with water twice and then with brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / acetone = 3/1) giving 1- (4-chlorobenzyl) -3- (2-methyl-2-oxiranylmethyl) imidazolidin-2-one (399 mg, 60%) as a light yellow oil.

[1526] ¹ H NMR (CDCb) δ ppm:

[1527] 1.35 (3H, s), 2.62 (1H, d, J = 4.7 Hz), 2.68 (1H, d, J = 4.7 Hz), 3.05 - 3, 25 (3H, m), 3.27 - 3.49 (2H, m), 3.61 (1H, d, J = 14.7 Hz), 4.35 (2H, s), 7.21 (2H , dd, J = 2.0 Hz, 6.7 Hz), 7.30 (2H, dd, J = 2.0 Hz, 6.7 Hz).

[1528] Using corresponding starting materials, compounds of Reference Examples 252 and 253 were prepared in the same manner as described in Reference Example 251.

Reference Example 252

- (1-benzylpipehdin-4-yl) -3- (2-methyl-2-oxiranylmethyl) imidazolin-2-one [1529] 54% yield [1530] ¹ H NMR (CDCb) δ ppm:

[1531] 1.35 (3H, s), 1.59 - 1.80 (4H, m), 2.00-2.16 (2H, m), 2.60 (1H, d, J = 4, 7

Hz), 2.66 (1H, d, J = 4.7 Hz), 2.84 - 3.00 (2H, m), 3.07 (1H, d, J = 14.7 Hz), 3, 22 - 3.43 (4H, m), 3.50 (2H, s), 3.54 (1H, d, J = 14.7 Hz), 3.68 - 3.86 (1H, m), 7 , 16 - 7.34 (5H, m).

Reference Example 253 1- (2,4-dimethoxybenzyl) -3- (2-methyl-2-oxiranylmethyl) imidazolin-2-one [1532] 40% yield [1533] ¹ H NMR (CDCb) δ ppm:

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482/854 [1534] 1.34 (3H, s), 2.60 (1H, d, J = 4.7 Hz), 2.67 (1H, d, J = 4.7 Hz), 3.10 (1H, d,

J = 14.6 Hz), 3.14-3.34 (4H, m), 3.56 (1H, d, J = 14.6 Hz), 3.80 (6H, s), 4.35 ( 2H, s), 6.32 - 6.43 (2H, m), 7.18 (1H, d, J = 8.9 Hz).

Reference Example 254

Preparation of 1- (2-methyl-2-oxiranylmethyl) pyrrolidine-2,5-dione [1535] Using 1- (2-methyl-2-propenyl) pyrrolidine-2,5-dione, 1- (2methyl) -2-oxiranylmethyl) pyrrolidine-2,5-dione in the same manner as described in Reference Example 228.

[1536] 86% yield [1537] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1538] 1.34 (3H, s), 2.58 (1H, d, J = 4.6 Hz), 2.67 - 2.79 (5H, m), 3.56 (1H, d, J =

13.9 Hz), 3.84 (1H, d, J = 13.9 Hz).

Reference Example 255

Preparation of 2- (2-methyl-2-oxiranylmethyl) phthalimide [1539] Using 2- (2-methyl-2-propenyl) phthalimide, 2- (2-methyl-2oxyranylmethyl) phthalimide was prepared in the same manner as described in Reference Example 228.

[1540] 98% yield [1541] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1542] 1.38 (3H, s), 2.62 (1H, d, J = 4.6 Hz), 2.82 (1H, d, J = 4.6 Hz), 3.71 (1H, d,

J = 14.3 Hz), 4.01 (1H, d, J = 14.3 Hz), 7.73 (2H, dd, J = 2.9 Hz, 8.6 Hz), 7.87 (2H , dd, J = 2.9 Hz, 8.6 Hz).

Reference Example 256

Preparation of 1- (2-methyl-2-oxiranylmethyl) -1 H-benzimidazole [1543] Using 1- (2-methyl-2-propenyl) -1 H-benzimidazole, 1- (2-methyl2-oxiranylmethyl) was prepared ) -1 H-benzimidazole in the same manner as described in Reference Example 228.

[1544] 11% yield [1545] ¹ H NMR (CDCb) δ ppm:

[1546] 1.32 (3H, s), 2.60 (1H, d, J = 4.4 Hz), 2.71 (1H, d, J = 4.4 Hz), 4.17 (1H, d,

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483/854

J = 15.1 Hz), 4.44 (1H, d, J = 15.1 Hz), 7.23 - 7.41 (2H, m), 7.48 (1H, dd, J = 2.2 Hz, 7.8 Hz), 7.80 (1H, dd, J = 2.2 Hz, 7.8 Hz), 7.93 (1H, s).

Reference Example 257

Preparation of 1- (2-methyl-2-oxiranylmethyl) -1 H-imidazole [1547] Using 1- (2-methyl-2-propenyl) -1 H-imidazole, 1- (2-methyl-2oxyranylmethyl) was prepared ) -1 H-imidazole in the same manner as described in Reference Example 228.

[1548] 53% yield [1549] ¹ H NMR (CDCb) δ ppm:

[1550] 1.26 (3H, s), 2.57 (1H, d, J = 4.4 Hz), 2.69 (1H, d, J = 4.4 Hz), 3.94 (1H, d,

J = 14.7 Hz), 4.16 (1H, d, J = 14.7 Hz), 6.97 (1H, s), 7.08 (1H, s), 7.49 (1H, s) .

Reference Example 258

Preparation of 3- [3- (2-methyl-2-oxiranyl) propyl] -3H-benzoxazol-2-one [1551] Using 3- (4-methyl-4-pentenyl) -3H-benzoxazol-2-one ( 3.4 g, 15.65 mmol), 3- [3- (2-methyl-2-oxiranyl) propyl] -3H-benzoxazol-2-one (3.8 g, quantitative) was prepared as a crystalline powder colorless in the same manner as described in Reference Example 228.

[1552] ¹ H NMR (CDCb) δ ppm:

[1553] 1.33 (3H, s), 1.56 - 1.77 (2H, m), 1.80 - 1.95 (2H, m), 2.59 (1H, d, J = 4, 8

Hz), 2.63 (1H, d, J = 4.8 Hz), 3.85 (2H, t, J = 7.4 Hz), 6.99 (1H, d, J = 7.9 Hz) , 7.05 7.23 (3H, m).

Reference Example 259

Preparation of 3- [4- (2-methyl-2-oxiranyl) butyl] -3H-benzoxazol-2-one [1554] Using 3- (5-methyl-5-hexenyl) -3H-benzoxazol-2-one ( 1.1 g, 4.8 mmol), 3- [4- (2-methyl-2-oxiranyl) butyl] -3H-benzoxazol-2-one (1.2 g, quantitative) was prepared as a colorless oil in the same way as described in Reference Example 228.

[1555] ¹ H NMR (CDCb) δ ppm:

[1556] 1.30 (3H, s), 1.42 - 1.67 (4H, m), 1.74 - 1.88 (2H, m), 2.57 (1H, d, J = 4, 9

Hz), 2.60 (1H, d, J = 4.9 Hz), 3.84 (2H, t, J = 7.2 Hz), 6.98 (1H, d, J = 8.1 Hz) , 7.02 Petition 870190039560, of 26/04/2019, p. 492/876

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7.30 (3H, m).

Reference Example 260

Preparation of 3- (2-methyl-2-oxiranylmethyl) oxazolidin-2-one [1557] Using 3- (2-methyl-2-propenyl) oxazolidin-2-one (4.28 g, 30.35 mmol), 3- (2-methyl-2-oxiranylmethyl) oxazolidin-2-one (2.87 g, 62% yield) was prepared as a colorless oil, by the method in Reference Example 228.

[1558] ¹ H NMR (CDCb) δ ppm:

[1559] 1.36 (3H, s), 2.66 (1H, d, J = 4.5 Hz), 2.70 (1H, d, J = 4.5 Hz), 3.15 (1H, d,

J = 14.7 Hz), 3.57 - 3.75 (3H, m), 4.25 - 4.39 (2H, m).

Reference Example 261

Preparation of 3,3-difluoro-1 - (2-methyl-2-oxiranylmethyl) -1,3-dihydroindol-2-one [1560] Using 3,3-difluoro-1- (2-methyl-2-propenyl) -1,3-dihydroindol-2-one (1.08 g, 4.83 mmol), 3,3-difluoro-1- (2-methyl-2-oxiranylmethyl) -1,3-dihydroindol-2 was prepared -one (1.14 g, 99% yield) as a light yellow powder in the same manner as described in Reference Example 228.

[1561] ¹ H NMR (CDCb) δ ppm:

[1562] 1.35 (3H, s), 2.71 (1H, d, J = 4.3 Hz), 2.77 (1H, d, J = 4.3 Hz), 3.46 (1H, d,

J = 15.0 Hz), 4.26 (1H, d, J = 15.0 Hz), 7.12-7.24 (2H, m), 7.45-7.61 (2H, m).

[1563] Using corresponding starting materials, compounds of Reference Examples 262 and 263 were prepared in the same manner as described in Reference Example 261.

Reference Example 262

3,3-dim ethyl-1 - (2-methyl-2-oxiranylmethyl) -1,3-dihydroindol-2-one [1564] ¹ H NMR (CDCb) δ ppm:

[1565] 1.31 (3H, s), 1.39 (6H, s), 2.67 (1H, d, J = 4.5 Hz), 2.74 (1H, d, J = 4.5 Hz),

3.53 (1H, d, J = 14.0 Hz), 4.22 (1H, d, J = 14.0 Hz), 7.00 - 7.10 (2H, m), 7.16 - 7 , 31 (2H, m).

Reference Example 263

- (2-methyl-2-oxiranylmethyl) -1,3-dihydroindol-2-one [1566] ¹ H NMR (CDCb) δ ppm:

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485/854 [1567] 1.34 (3H, s), 2.67 (1H, d, J = 4.5 Hz), 2.76 (1H, d, J = 4.5 Hz), 3.49 - 3.61 (3H, m), 4.22 (1H, d, J = 14.9 Hz), 7.00 - 7.10 (2H, m), 7.18 - 7.35 (2H, m ).

Reference Example 264

Preparation of benzyl (2-methyl-2-oxiranylmethyl) carbamate [1568] Benzyl N- (2-methyl-2-propenyl) carbamate (3.90 g, 19.0 mmol) prepared in Reference Example 173 was dissolved in methylene chloride (80 ml), to which m-chloroperbenzoic acid (5.15 g, 20.9 mmol) was added, and the mixture was stirred at room temperature overnight. Aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, which was stirred for some time. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure giving benzyl (2-methyl-2-oxiranylmethyl) carbamate (4.31 g, quantitative) as a colorless oil.

[1569] ¹ H NMR (CDCb) δ ppm:

[1570] 1.35 (3H, s), 2.61 (1H, d, J = 4.5 Hz), 2.72 (1H, d, J = 4.5 Hz), 3.28 - 3, 53 (2H, m), 4.90 (1H, br), 5.11 (2H, s), 7.26 - 7.44 (5H, m).

[1571] Using corresponding starting materials, compounds of Reference Examples 265 to 276 were prepared in the same manner as described in Reference Example 264.

Reference Example 265

Benzyl N-methyl-N- (2-methyl-2-oxiranylmethyl) carbamate [1572] 42% yield [1573] ¹ H NMR (CDCb) δ ppm:

[1574] 1.26 (1.5H, s), 1.31 (1.5H, s), 2.57 (1H, s), 2.61 (1H, s), 2.99 (3H, s ), 3.24 (1H, d, J = 15.1 Hz), 3.62 (0.5H, d, J = 15.1 Hz), 3.72 (0.5H, d, J = 15, 1 Hz), 5.14 (2H, s), 7.27-7.41 (5H, m).

Reference Example 266

4-chlorobenzyl (2-methyl-2-oxiranylmethyl) carbamate [1575] 98% yield

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486/854 [1576] ¹ H NMR (CDCb) δ ppm:

[1577] 1.35 (3H, s), 2.62 (1H, d, J = 4.4 Hz), 2.71 (1H, d, J = 4.4 Hz), 3.27 - 3, 50 (2H, m), 4.88 (1H, br), 5.06 (2H, s), 7.23 - 7.41 (4H, m).

Reference Example 267

4-fluorobenzyl (2-methyl-2-oxiranylmethyl) carbamate [1578] 100% yield [1579] ¹ H NMR (CDCb) δ ppm:

[1580] 1.34 (3H, s), 2.61 (1H, d, J = 4.5 Hz), 2.71 (1H, d, J = 4.5 Hz), 3.32 - 3, 50 (2H, m), 4.86 (1H, br), 5.06 (2H, s), 6.95 - 7.09 (2H, m), 7.27 - 7.41 (2H, m) .

Reference Example 268 ethyl (2-methyl-2-oxiranylmethyl) carbamate [1581] 82% yield [1582] ¹ H NMR (CDCb) δ ppm:

[1583] 1.24 (3H, t, J = 7.1 Hz), 1.35 (3H, s), 2.62 (1H, d, J = 4.5 Hz), 2.74 (1H, d,

J = 4.5 Hz), 3.27 - 3.50 (2H, m), 4.12 (2H, q, J = 7.1 Hz), 4.78 (1H, br).

Reference Example 269 4-tnfluoromethoxybenzyl (2-methyl-2-oxiranylmethyl) carbamate [1584] 99% yield [1585] ¹ H NMR (CDCb) δ ppm:

[1586] 1.35 (3H, s), 2.62 (1H, d, J = 4.4 Hz), 2.71 (1H, d, J = 4.4 Hz), 3.42 (2H, d,

J = 5.6 Hz), 4.90 (1H, br), 5.10 (2H, s), 7.20 (2H, d, J = 8.3 Hz), 7.38 (2H, d, J = 8.3 Hz).

Reference Example 270

4-Fluorobenzyl N-methyl-N- (2-methyl-2-oxiranylmethyl) carbamate [1587] 73% yield [1588] ¹ H NMR (CDCb) δ ppm:

[1589] 1.25 (1.5H, s), 1.30 (1.5H, s), 2.56 (1H, s), 2.61 (1H, s), 2.97 (3H, s ), 3.22 (1H, d, J = 14.8 Hz), 3.61 (0.5H, d, J = 14.8 Hz), 3.72 (0.5H, d, J = 14, 8 Hz), 5.10 (2H, s), 6.95 - 7.09 (2H, m), 7.27 - 7.41 (2H, m).

Reference Example 271

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487/854 4-chlorobenzyl oxiranylmethylcarbamate [1590] 97% yield [1591] ¹ H NMR (CDCb) δ ppm:

[1592] 2.59 (1H, dd, J = 2.6 Hz, 4.6 Hz), 2.79 (1H, t, J = 4.3 Hz), 3.11 (1H, br), 3 , 20

- 3.32 (1H, m), 3.50 - 3.73 (1H, m), 4.93 (1H, br), 5.07 (2H, s), 7.23 - 7.41 (4H , m). Reference Example 272 4-fluorobenzyl oxiranylmethylcarbamate [1593] 89% yield [1594] ¹ H NMR (CDCb) δ ppm:

[1595] 2.59 (1H, dd, J = 2.6 Hz, 4.6 Hz), 2.79 (1H, t, J = 4.3 Hz), 3.11 (1H, br), 3 , 21

- 3.32 (1H, m), 3.45 - 3.73 (1H, m), 4.92 (1H, br), 5.07 (2H, s), 6.95 - 7.09 (2H , m), 7.27 -7.41 (2H, m).

Reference Example 273

4-fluorobenzyl N-methyl-N-oxiranylmethylcarbamate [1596] 34% yield [1597] ¹ H NMR (CDCb) δ ppm:

[1598] 2.51 (1H, br), 2.76 (1H, br), 3.01 (3H, s), 3.02 - 3.27 (2H, m), 3.55 - 3.91 (1H, m), 5.10 (2H, s), 6.95-7.09 (2H, m), 7.27-7.41 (2H, m).

Reference Example 274 ter-butyl oxiranylmethylcarbamate [1599] 83% yield [1600] ¹ H NMR (CDCb) δ ppm:

[1601] 1.45 (9H, s), 2.59 (1H, dd, J = 2.6 Hz, 4.6 Hz), 2.78 (1H, t, J = 4.4 Hz), 3 .09 (1H, br), 3.16-3.28 (1H, m), 3.38 - 3.66 (1H, br), 4.53-4.91 (1H, br).

Reference Example 275 benzyl oxiranylmethylcarbamate [1602] 72% yield [1603] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1604] 2.67 (1H, t, J = 4.5 Hz), 2.91 - 3.32 (4H, m), 4.91 - 5.09 (3H, m), 7.23 - 7 , 55 (5H, m).

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488/854

Reference Example 276 phenyl oxiranylmethylcarbamate [1605] 90% yield [1606] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1607] 2.57 (1H, dd, J = 2.5 Hz, 5.0 Hz), 2.73 (1H, t, J = 4.5 Hz), 3.00 - 3.45 (3H,

m), 7.10 (2H, d, J = 7.6 Hz), 7.20 (1H, t, J = 7.6 Hz), 7.38 (2H, t, J = 7.6 Hz) , 7.94 (1H, br).

Reference Example 277

Preparation of (2-methyl-2-oxiranylmethyl) (4-chlorophenyl) carbamate [1608] M-chloroperbenzoic acid (1.6 g, 6.6 mmol) was added to a solution of

2-methyl-2-propenyl (4-chlorophenyl) carbamate (1.0 g, 4.4 mmol) in methylene chloride (20 ml) while cooling in an ice bath, and the mixture was stirred at room temperature for 4 hours. To this was added aqueous sodium thiosulfate solution and the mixture was filtered, and aqueous sodium hydrogen carbonate solution was added to the filtrate. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give (2-methyl-2-oxiranylmethyl) (4-chlorophenyl) carbamate (1.1 g, quantitative) as a light yellow crystalline powder.

[1609] ¹ H NMR (CDCb) δ ppm:

[1610] 1.42 (3H, s), 2.71 (1H, d, J = 4.6 Hz), 2.82 (1H, d, J = 4.6 Hz), 4.01 (1H, d,

J = 11.9 Hz), 4.37 (1H, d, J = 11.9 Hz), 6.79 (1H, br), 7.23 - 7.37 (4H, m).

Reference Example 278

Preparation of (2-methyl-2-oxiranylmethyl) N- (4-chlorophenyl) -N-methylcarbamate [1611] m-chloroperbenzoic acid (2.5 g, 10.1 mmol) was added to a solution of 2-methyl -2-propenyl N- (4-chlorophenyl) -N-methylcarbamate (1.78 g, 6.7 mmol) in methylene chloride (20 ml) while cooling in an ice bath, and the mixture was stirred at temperature 6.5 hours. To this was added aqueous sodium thiosulfate solution and the mixture was filtered, and aqueous sodium hydrogen carbonate solution was added to the filtrate. The organic layer was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (chloride

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489/854 methylene / methanol = 20/1) giving (2-methyl-2-oxiranylmethyl) N- (4-chlorophenyl) -Nmethylcarbamate (1.7 g, quantitative) as a light yellow oil.

[1612] ¹ H NMR (CDCb) δ ppm:

[1613] 1.32 (3H, s), 2.62 (1H, d, J = 4.6 Hz), 2.69 (1H, d, J = 4.6 Hz), 3.30 (3H, s),

3.99 (1H, d, J = 11.8 Hz), 4.30 (1H, d, J = 11.8 Hz), 7.15 - 7.25 (2H, m), 7.31 - 7 , 38 (2H, m).

Reference Example 279

Preparation of tert-butyl 4-oxiranylmethylpiperazine-1-carboxylate [1614] A mixture of tert-butyl piperazine-1-carboxylate (6.2 g, 33.29 mmol), epibromohydrin (5.4 g, 39.42 mmol) and potassium carbonate (5.5 g, 39.79 mmol) in acetonitrile (70 ml) was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) giving ter-butyl 4-oxiranylmethylpiperazine-1-carboxylate (6.2 g, 77% yield) as a colorless oil.

[1615] ¹ H NMR (CDCb) δ ppm:

[1616] 1.46 (9H, s), 2.21 -2.60 (6H, m), 2.70-2.81 (2H, m), 3.05 - 3.12 (1H, m) ,

3.35-3.56 (4H, m).

Reference Example 280

Preparation of ter-butyl [4- (2-methyl-2-oxiranylmethyl) piperazin-1-yl] [1617] A mixture of (2-methyl-2-oxiranylmethyl) toluene-4-sulfonate (9.75 g , 40.3 mmol), ter-butyl piperazin-1-yl-carbamate (6.75 g, 33.5 mmol) prepared in Reference Example 36, triethylamine (7 ml, 50.3 mmol) and potassium iodide (6.68 g, 33.5 mmol) in DMF (70 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / acetone = 4/1) giving [4- (2-methyl-2

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490/854 oxiranylmethyl) piperazin-1-yl] tert-butyl carbamate (4.66 g, 51% yield) as a colorless crystalline powder.

[1618] ¹ H NMR (CDCb) δ ppm:

[1619] 1.35 (3H, s), 1.46 (9H, s), 2.31 (1H, d, J = 12.9 Hz), 2.49 - 2.84 (11H, m),

5.37 (1H, br).

Reference Example 281

Preparation of 3- (2-methyl-2-oxiranylmethyl) -5- (4-trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazol-2-one [1620] A mixture of 5- (4-trifluoromethoxyphenyl) - 3H- [1,3,4] oxadiazol-2-one (3.18 g, 12.92 mmol) prepared in Reference Example 49, (2-methyl-2-oxiranylmethyl) toluene-4-sulfonate (4.80 g, 19.38 mmol), potassium carbonate (2.14 g, 15.50 mmol) and sodium iodide (2.90 g, 19.38 mmol) in DMF (30 ml) was stirred at room temperature for 24 hours, and then at 60 ° C for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 9/1) giving 3- (2-methyl-2-oxiranylmethyl) -5- (4thfluoromethoxyphenyl) -3H- [1,3 , 4] oxadiazole-2-one (2.37 g, 58% yield) as a colorless crystalline powder.

[1621] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1622] 1.43 (3H, s), 2.72 (1H, d, J = 4.4 Hz), 2.86 (1H, d, J = 4.4 Hz), 3.93 (2H, dd,

J = 14.8 Hz, 22.2 Hz), 7.28 - 7.41 (2H, m), 7.83 - 7.98 (2H, m).

[1623] Using 5-substituted-3H- [1,3,4] oxadiazol-2-one and (2-methyl-2oxyranylmethyl) toluene-4-sulfonate, compounds of Reference Examples 282 to 289 were prepared therefrom as described in Reference Example 281.

Reference Example 282

3- (2-methyl-2-oxiranylmethyl) -5-phenyl-3H- [1,3,4] oxadiazol-2-one [1624] 41% yield [1625] ¹ H NMR (CDCb) δ ppm:

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491/854 [1626] 1.44 (3H, s), 2.72 (1H, d, J = 4.5 Hz), 2.88 (1H, d, J = 4.5 Hz), 3.87 (1H, d,

J = 14.7 Hz), 3.99 (1H, d, J = 14.7 Hz), 7.40 - 7.57 (3H, m), 7.79 - 7.87 (2H, m). Reference Example 283

3- (2-methyl-2-oxiranylmethyl) -5- (4-trifluoromethylphenyl) -3H- [1,3,4] oxadiazol-2-one [1627] 34% yield [1628] ¹ H NMR (CDCb) δ ppm:

[1629] 1.45 (3H, s), 2.73 (1H, d, J = 4.5 Hz), 2.87 (1H, d, J = 4.5 Hz), 3.92 (1H, d,

J = 14.8 Hz), 4.00 (1H, d, J = 14.8 Hz), 7.75 (2H, d, J = 8.3 Hz), 8.01 (2H, d, J = 8.3 Hz).

Reference Example 284

3- (2-methyl-2-oxiranylmethyl) -5- (4-biphenylyl) -3H- [1,3,4] oxadiazol-2-one [1630] 38% yield [1631] ¹ H NMR (CDCb) δ ppm:

[1632] 1.45 (3H, s), 2.73 (1H, d, J = 4.5 Hz), 2.89 (1H, d, J = 4.5 Hz), 3.89 (1H, d,

J = 14.8 Hz), 4.00 (1H, d, J = 14.8 Hz), 7.33 - 7.50 (3H, m), 7.57 - 7.75 (4H, m), 7.93 (2H, d, J = 8.6 Hz).

Reference Example 285

3- (2-methyl-2-oxiranylmethyl) -5- (4-chlorophenyl) -3H- [1,3,4] oxadiazol-2-one [1633] 52% yield [1634] ¹ H NMR (CDCb) δ ppm:

[1635] 1.44 (3H, s), 2.72 (1H, d, J = 4.4 Hz), 2.86 (1H, d, J = 4.4 Hz), 3.89 (1H, d,

J = 14.8 Hz), 3.97 (1H, d, J = 14.8 Hz), 7.46 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.7 Hz).

Reference Example 286

3- (2-methyl-2-oxiranylmethyl) -5- (4-fluorophenyl) -3H- [1,3,4] oxadiazol-2-one [1636] 72% yield [1637] ¹ H NMR (CDCb) δ ppm:

[1638] 1.43 (3H, s), 2.72 (1H, d, J = 4.5 Hz), 2.87 (1H, d, J = 4.5 Hz), 3.88 (1H, d,

J = 14.7 Hz), 3.96 (1H, d, J = 14.7 Hz), 7.11 - 7.21 (2H, m), 7.74 - 7.89 (2H, m). Reference Example 287

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492/854

3- (2-methyl-2-oxiranylmethyl) -5- [2- (4-chlorophenyl) ethyl] -3H- [1,3,4] oxadiazol-2-one [1639] 78% yield [1640] ¹ H NMR (CDCb) δ ppm:

[1641] 1.32 (3H, s), 2.64 (1H, d, J = 4.5 Hz), 2.72 (1H, d, J = 4.5 Hz), 2.79 - 2, 90 (2H, m), 2.93 - 3.04 (2H, m), 3.74 (1H, d, J = 14.8 Hz), 3.79 (1H, d, J = 14.8 Hz ), 7.12 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz).

Reference Example 288

3- (2-methyl-2-oxiranylmethyl) -5- [2- (4-chlorophenyl) vinyl] -3H- [1,3,4] oxadiazol-2-one [1642] 100% yield [1643] ¹ H NMR (CDCb) δ ppm:

[1644] 1.41 (3H, s), 2.71 (1H, d, J = 4.4 Hz), 2.83 (1H, d, J = 4.4 Hz), 3.88 (2H, s),

6.60 (1H, d, J = 16.4 Hz), 7.28 - 7.47 (5H, m).

Reference Example 289 3- (2-methyl-2-oxiranylmethyl) -5- (4-chlorophenoxymethyl) -3H- [1,3,4] oxadiazol-2-one [1645] 59% yield [1646] ¹ H NMR (CDCb) δ ppm:

[1647] 1.37 (3H, s), 2.68 (1H, d, J = 4.4 Hz), 2.78 (1H, d, J = 4.4 Hz), 3.86 (2H, s),

4.90 (2H, s), 6.91 (2H, dd, J = 2.3 Hz, 6.9 Hz), 7.29 (2H, dd, J = 2.3 Hz, 6.9 Hz) . Reference Example 290

Preparation of 2- (2-methyl-2-oxiranylmethyl) -1,1-dioxo-1,2-dihydrobenzo [d] isothiazol-3-one [1648] Using saccharin and (2-methyl-2-oxiranylmethyl) toluene- 4-sulfonate, 2- (2-methyl-2-oxiranylmethyl) -1,1-dioxo-1,2-dihydrobenzo [d] isothiazole-3-one was prepared in the same manner as described in Reference Example 281.

[1649] a colorless crystalline powder, 43% yield [1650] ¹ H NMR (CDCb) δ ppm:

[1651] 1.49 (3H, s), 2.74 (1H, d, J = 4.5 Hz), 2.96 (1H, d, J = 4.5 Hz), 3.73 (1H, d,

J = 15.5 Hz), 4.04 (1H, d., J = 15.5 Hz), 7.81 -8.00 (3H, m), 8.09 (1H, dd, J = 2, 4 Hz, 6.6 Hz).

Reference Example 291

Preparation of 1- (2-methyl-2-oxiranylmethyl) piperidin-4-one

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493/854 [1652] Using 4-piperidone hydrochloride hydrochloride, 1- (2methyl-2-oxiranylmethyl) piperidin-4-one was prepared in the same manner as described in Reference Example 281.

[1653] a colorless oil, 50% yield [1654] ¹ H NMR (CDCb) δ ppm:

[1655] 1.43 (3H, s), 2.35 - 2.51 (5H, m), 2.58 - 2.93 (7H, m).

Reference Example 292

Preparation of 4- (2-methyl-2-oxiranylmethyl) -1- (4-trifluoromethylbenzyl) piperazine-2-one [1656] Using 1- (4-trifluoromethylbenzyl) piperazine-2-one, 4- (2methyl) was prepared -2-oxiranylmethyl) -1- (4-trifluoromethylbenzyl) piperazine-2-one prepared in the same manner as described in Reference Example 281.

[1657] a colorless crystalline powder, 63% yield [1658] ¹ H NMR (CDCb) δ ppm:

[1659] 1.37 (3H, s), 2.34 (1H, d, J = 12.9 Hz), 2.53 - 2.67 (4H, m), 2.77 - 2.91 (1H ,

m), 3.14-3.37 (4H, m), 4.62 (1H, d, J = 15.1 Hz), 4.69 (1H, d, J = 15.1 Hz), 7, 38 (2H, d, J = 8.2 Hz), 7.60 (2H, d, J = 8.2 Hz).

Reference Example 293

Preparation of 4- (2-methyl-2-oxiranylmethyl) -1 - (ter-butyl) piperazine-2-one [1660] Using 1- (ter-butyl) piperazine-2-one, 4- (2 -methyl-2oxyranylmethyl) -1- (ter-butyl) piperazine-2-one in the same manner as described in Reference Example 281.

[1661] a colorless crystalline powder, 39% yield [1662] ¹ H NMR (CDCb) δ ppm:

[1663] 1.38 (3H, s), 1.45 (9H, s), 2.31 (1H, d, J = 12.9 Hz), 2.42 - 2.55 (4H, m),

2.74 - 2.88 (1H, m), 3.02 (1H, d, J = 16.1 Hz), 3.20 (1H, d, J = 16.1 Hz), 3.28 - 3 , 37 (2H, m).

Reference Example 294

Preparation of (S) -1- (2-methyl-2-oxiranylmethyl) -4- (4-trifluoromethoxyphenyl) piperazine [1664] A solution of (2-methyl-2-oxiranylmethyl) (R) -toluene-4-sulfonate (0.80 g,

3.30 mmol), 1- (4-trifluoromethoxyphenyl) piperazine (0.91 g, 3.36 mmol), and triethylamine

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494/854 (0.55 ml, 3.96 mmol) in DMF (8 ml) was stirred at room temperature for 22 hours. The reaction mixture was poured into water, and extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving (S) -1 - (2-methyl-2-oxiranylmethyl) -

4- (4-trifluoromethoxyphenyl) piperazine (0.46 g, 44% yield) as a light yellow oil.

[1665] ¹ H NMR (CDCb) δ ppm:

[1666] 1.40 (3H, s), 2.34 (1H, d, J = 12.9 Hz), 2.52-2.77 (7H, m), 3.10-3.27 (4H ,

m), 6.81 - 6.94 (2H, m), 7.06 - 7.17 (2H, m).

Reference Example 295

Preparation of ethyl (S) -1 - (2-methyl-2-oxiranylmethyl) piperidine-4-carboxylate [1667] A solution of (2-methyl-2-oxiranylmethyl) (R) -toluene-4-sulfonate (13, 5 g,

55.8 mmol), ethyl piperidine 4-carboxylate (8.9 g, 50.9 mmol), and triethylamine (6.5 g, 64.4 mmol) in DMF (70 ml) was stirred at room temperature for 2 days. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/1) giving ethyl (S) 1- (2-methyl-2-oxiranylmethyl) piperidine-4-carboxylate (5 , 4 g, 47% yield) as a colorless oil.

[1668] ¹ H NMR (CDCb) δ ppm:

[1669] 1.25 (3H, t, J = 7.1 Hz), 1.36 (3H, s), 1.67 - 1.93 (4H, m), 1.97 -2.08 (2H ,

m), 2.19 - 2.37 (2H, m), 2.48 (1H, d, J = 11.5 Hz), 2.58 (2H, s), 2.78 - 2.97 (2H , m), 4.13 (2H, q, J = 7.1 Hz).

[1670] Using corresponding starting materials, compounds of Reference Examples 296 to 299 were prepared in the same manner as described in Reference Example 295.

Reference Example 296

4-trifluoromethylbenzyl (S) -1- (2-methyl-2-oxiranylmethyl) piperidine-4-carboxylate

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495/854 [1671] a colorless oil, 18% yield [1672] ¹ H NMR (CDCb) δ ppm:

[1673] 1.35 (3H, s), 1.69 - 2.10 (6H, m), 2.25 - 2.37 (1H, m), 2.28 (1H, d, J = 12, 9

Hz), 2.48 (1H, d, J = 12.9 Hz), 2.58 (2H, s), 2.81 - 3.00 (2H, m), 5.11 (2H, s), 7.20 (2H, d, J = 8.0 Hz), 7.38 (2H, d, J = 8.0 Hz).

Reference Example 297 4-chlorobenzyl (S) -1- (2-methyl-2-oxiranylmethyl) piperidine-4-carboxylate [1674] a colorless oil, 26% yield [1675] ¹ H NMR (CDCb) δ ppm:

[1676] 1.36 (3H, s), 1.75-2.16 (7H, m), 2.27 (1H, d, J = 12.9 Hz), 2.50 (1H, d, J =

12.9 Hz), 2.58 (2H, s), 2.87 - 3.09 (2H, m), 5.13 (2H, s), 7.17 - 7.21 (2H, m), 7.27 -

7.31 (2H, m).

Reference Example 298

N- (4-chlorobenzyl) (S) -1 - (2-methyl-2-oxiranylmethyl) piperidine-4-carboxamide [1677] a colorless oil, 26% yield [1678] ¹ H NMR (CDCb) δ ppm:

[1679] 1.36 (3H, s), 1.75-2.16 (7H, m), 2.27 (1H, d, J = 12.9 Hz), 2.50 (1H, d, J =

12.9 Hz), 2.58 (2H, s), 2.87 - 3.09 (2H, m), 4.41 (2H, d, J = 5.8 Hz), 5.78 (1H, br), 7.17 -7.21 (2H, m), 7.27-7.31 (2H, m).

Reference Example 299

N- (4-chlorophenyl) (S) -1- (2-methyl-2-oxiranylmethyl) piperidine-4-carboxamide [1680] a colorless oil, 33% yield [1681] ¹ H NMR (CDCb) δ ppm:

[1682] 1.37 (3H, s), 1.82 -2.08 (6H, m), 2.13-2.27 (1H, m), 2.30 (1H, d, J = 13, 0

Hz), 2.53 (1H, d, J = 13.0 Hz), 2.60 (2H, s), 2.93 - 3.12 (2H, m), 7.16 (1H, bs), 7.26 -

7.31 (2H, m), 7.45-7.49 (2H, m).

Reference Example 300

Preparation of 5- (2-methyl-2-oxiranylmethylsulfanyl) -1-phenyl-1 H-tetrazole [1683] A mixture of 1-phenyl-5-mercapto-1 H-tetrazole (3.5 g, 19.64 mmol ), (2methyl-2-oxiranylmethyl) toluene-4-sulfonate (5 g, 20.64 mmol), potassium carbonate (3

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496/854 g, 21.71 mmol), and sodium iodide (4.5 g, 30.02 mmol) in DMF (30 ml) was stirred at 60 ° C for 6 hours. The reaction mixture was poured into water, and extracted with ethyl acetate twice. The extracts were combined, washed with 5% aqueous sodium hydroxide solution and then with water three times, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (nhexane / ethyl acetate = 2/1) giving 5- (2-methyl-2-oxiranylmethylsulfanyl) -1-phenyl-1 Htetrazole (1.9 g, 39% yield) as a colorless oil.

[1684] ¹ H NMR (CDCb) δ ppm:

[1685] 1.46 (3H, s), 2.73 (1H, d, J = 4.5 Hz), 2.91 (1H, d, J = 4.5 Hz), 3.61 (1H, d,

J = 13.9 Hz), 3.77 (1H, d, J. = 13.9 Hz), 7.50 - 7.65 (5H, m).

Reference Example 301

Preparation of tert-butyl 3- (2-methyl-2-oxiranyl) propionate [1686] Trimethylsulfoxonium iodide (19.54 g, 88.78 mmol) was added to a sodium hydride suspension (3.71 g , 92.82 mmol) in DMSO (50 ml) while cooling in an ice bath, and the mixture was stirred for 2.5 hours. To this was added a solution of tert-butyl 4-oxopentanoate (13.90 g, 80.71 mmol) in DMSO (20 ml), and the mixture was stirred at room temperature for 15 hours. The mixture was poured into ice water, extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure giving tert-butyl 3- (2-methyl-2-oxiranyl) propionate (10.1 g, 67% yield) as a yellow oil clear.

[1687] ¹ H NMR (CDCb) δ ppm:

[1688] 1.32 (3H, s), 1.44 (9H, s), 1.85-1.94 (2H, m), 2.27 - 2.33 (2H, m), 2.58 (1H, d, J = 4.7 Hz), 2.63 (1H, d, J = 4.7 Hz).

Reference Example 302

Preparation of 2-isopropyl-2-methoxymethoxymethyloxirane [1689] M-chloroperbenzoic acid (213 g, 861 mmol) was gradually added to a solution of 2-methoxymethoxymethyl-3-methyl-1-butene (89 g, 615 mmol) in methylene chloride (800 ml) while cooling in an ice bath, and the mixture was stirred

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497/854 at room temperature for 18 hours. The reaction mixture was washed with 10% aqueous potassium sulfide solution and aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and then concentrated under reduced pressure giving 2-isopropyl-2-methoxymethoxymethyloxirane (98 g, quantitative) as a colorless oil.

[1690] ¹ H NMR (CDCb) δ ppm:

[1691] 0.95 (3H, d, J = 7.0 Hz), 1.02 (3H, d, J = 7.0 Hz), 1.84 - 2.05 (1H, m), 2, 66 (1H, d, J = 4.9 Hz), 2.75 (1H, d, J = 4.9 Hz), 3.37 (3H, s), 3.63 (1H, d, J = 11 , 3 Hz), 3.70 (1H, d, J = 11.3 Hz), 4.62 (2H, s).

Reference Example 303

Preparation of 2-ethyl-2-methoxymethoxymethyloxirane [1692] M-chloroperbenzoic acid (143.7 g, 833 mmol) was gradually added to a solution of 2-methoxymethoxymethyl-1-butene (98 g, 757 mmol) prepared in the Example Reference 206 in methylene chloride (8800 ml) while cooling in an ice bath, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water, 10% aqueous sodium sulfide solution and aqueous sodium hydrogen carbonate solution, dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 2-ethyl-2-methoxymethoxymethyloxirane (111 g, quantitative) as a colorless oil.

[1693] ¹ H NMR (CDCb) δ ppm:

[1694] 0.96 (3H, t, J = 7.5 Hz), 1.60 - 1.73 (1H, m), 1.77 - 1.93 (1H, m), 2.66 (1H , d, J = 4.8 Hz), 2.74 (1H, d, J = 4.8 Hz), 3.37 (3H, s), 3.56 (1H, d, J = 11.2 Hz ), 3.65 (1H, d, J = 11.2 Hz), 4.64 (2H, s).

Reference Example 304

Preparation of 2- (2-methoxymethoxyethyl) oxirane [1695] M-chloroperbenzoic acid (20.6 g, 95.6 mmol) was gradually added to a solution of 4-methoxymethoxy-1-butene (10.46 g, 90 , 1 mmol) in methylene chloride (250 ml) while cooling in an ice bath, the mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered, and the filtrate was washed with 10% aqueous sodium sulfide solution and aqueous

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498/854 sodium hydrogen carbonate, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 2- (2-methoxymethoxyethyl) oxirane (10.3 g, 86%) as a colorless oil.

[1696] ¹ H NMR (CDCb) δ ppm:

[1697] 1.69 - 1.96 (2H, m), 2.53 (1H, dd, J = 2.7 Hz, 4.9 Hz), 2.79 (1H, t, J = 4.9

Hz), 3.02 - 3.08 (1H, m), 3.38 (3H, s), 3.68 (2H, t, J = 5.9 Hz), 4.64 (2H, s).

Reference Example 305

Preparation of 4- (4-trifluoromethylphenoxy) pipendin-1-carbonyl chloride [1698] A mixture of 4- (4-trifluoromethylphenoxy) piperidine (0.6 g, 2.45 mmol), triphosgene (0.25 g, 0 , 86 mmol), and pyridine (0.4 ml, 4.90 mmol) in toluene (6 ml) was heated to reflux for 2.5 hours. To this was added ethyl acetate, and the mixture was washed with 10% hydrochloric acid, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 4- (4trifluoromethylphenoxy) pipendin-1-carbonyl chloride (0.72 g, 96% yield) as a light yellow oil.

[1699] ¹ H NMR (CDCb) δ ppm:

[1700] 1.79-2.10 (4H, m), 3.50-3.96 (4H, m), 4.58-4.75 (1H, m), 6.97 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz).

Reference Example 306

Preparation of 4- (4-trifluoromethylphenylamino) piperidine-1-carbonyl chloride [1701] A mixture of (4-trifluoromethylphenylamino) pipendin (1.14 g, 4.67 mmol), triphosgene (0.55 g, 1.87 mmol), and triethylamine (0.98 ml, 7.01 mmol) in methylene chloride (10 ml) was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure giving 4- (4trifluoromethylphenylamino) pipendin-1-carbonyl chloride (1.43 g, quantitative) as a light yellow oil.

[1702] ¹ H NMR (CDCb) δ ppm:

[1703] 1.33 -1.65 (2H, m), 2.09 - 2.24 (2H, m), 3.02 - 3.22 (1H, m), 3.22 - 3.41 ( 1H,

m), 3.48 - 3.70 (1H, m), 4.20 - 4.35 (2H, m), 6.66 (2H, d, J = 8.5 Hz), 7.43 (2H , d, J =

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499/854

8.5 Hz).

[1704] As shown in Reference Example 305 or 306, amines, cyclic amines, and heterocyclic compounds condensed on benzene were allowed to react in the presence of triphosgene and triethylamine or pyridine giving compounds of Reference Examples 307 to 324.

Reference Example 307 5-chloro-2,3-dihydroindol-1-carbonyl chloride [1705] a light yellow crystalline powder, 100% yield [1706] ¹ H NMR (CDCb) δ ppm:

[1707] 3.19 (2H, t, J = 8.3 Hz), 4.28 (2H, t, J = 8.3 Hz), 7.18 - 7.22 (2H, m), 7, 80 (1H, d, J = 9.5 Hz).

Reference Example 308 6-chloro-3,4-dihydro-1 H-isoquinoline-2-carbonyl [1708] a light yellow oil, 100% yield [1709] ¹ H NMR (CDCb) δ ppm:

[1710] 2.83 - 3.00 (2H, m), 3.83 (1H, t, J = 6.0 Hz), 3.90 (1H, t, J = 6.0 Hz), 4, 71 (1H, s), 4.80 (1H, s), 7.06 (1H, d, J = 8.0 Hz), 7.13-7.28 (2H, m).

Reference Example 309 6-chloro-3,4-dihydro-2H-quinoline-1-carbonyl chloride [1711] a yellow oil, 100% yield [1712] ¹ H NMR (CDCb) δ ppm:

[1713] 1.99 - 2.09 (2H, m), 2.79 (2H, t, J = 6.5 Hz), 3.94 (2H, t, J = 6.3 Hz), 7, 14 7.20 (2H, m), 7.62 (1H, d, J = 8.5 Hz).

Reference Example 310 5-chloro-1,3-dihydroisoindol-2-carbonyl chloride [1714] a yellow oil, 100% yield [1715] ¹ H NMR (CDCb) δ ppm:

[1716] 3.19 (2H, t, J = 8.3 Hz), 4.28 (2H, t, J = 8.3 Hz), 7.18 - 7.22 (2H, m), 7, 80 (1H, d, J = 9.5 Hz).

Reference Example 311

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500/854

Tert-butyl 4-chlorocarbonylpiperazine-1-carboxylate [1717] a light yellow crystalline powder, 100% yield [1718] ¹ H NMR (CDCb) δ ppm:

[1719] 1.47 (9H, s), 3.16 - 3.29 (2H, m), 3.37 - 3.55 (4H, m), 3.55 - 3.78 (2H, m) .

Reference Example 312 4- (4-trifluoromethoxybenzyloxycarbonyl) piperazine-1-carbonyl chloride [1720] 100% yield [1721] ¹ H NMR (CDCb) δ ppm:

[1722] 3.43 - 3.80 (8H, m), 5.15 (2H, s), 7.15 - 7.25 (2H, m), 7.33 - 7.45 (2H, m) .

Reference Example 313 4- [3- (4-trifluoromethylphenyl) -2-propenyloxycarbonyl] piperazine-1-carbonyl chloride [1723] 100% yield [1724] ¹ H NMR (CDCb) δ ppm:

[1725] 3.54 - 3.65 (4H, m), 3.65 - 3.72 (2H, m), 3.72 - 3.83 (2H, m), 4.80 (2H, dd,

J = 1.1 Hz, 6.1 Hz), 6.39 (1H, dt, J = 6.1 Hz, 15.9 Hz), 6.68 (1H, d, J = 15.9 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8.4 Hz).

Reference Example 314 4- (4-chlorobenzyl) piperazine-1-carbonyl chloride [1726] a brown oil, 100% yield [1727] ¹ H NMR (CDCb) δ ppm:

[1728] 2.65 - 2.96 (4H, m), 3.67 - 4.08 (6H, m), 7.36 - 7.39 (4H, m).

Reference Example 315 4- (4-trifluoromethylbenzyl) piperazine-1-carbonyl chloride [1729] a brown oil, 100% yield [1730] ¹ H NMR (CDCb) δ ppm:

[1731] 2.97 - 3.12 (4H, m), 3.91 - 4.06 (2H, m), 4.06 - 4.21 (2H, m), 4.15 (2H, s) ,

7.58-7.73 (4H, m).

Reference Example 316 4- (4-trifluoromethoxybenzyl) piperazine-1-carbonyl chloride [1732] a brown oil, 100% yield

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501/854 [1733] ¹ H NMR (CDCb) δ ppm:

[1734] 2.58 -2.85 (4H, m), 3.58 - 3.90 (6H, m), 7.17-7.25 (2H, m), 7.35 - 7.46 ( 2H,

m).

Reference Example 317 4- (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridine-l-carbonyl chloride [1735] a light brown oil, 57% yield [1736] ¹ H NMR (CDCb) δ ppm :

[1737] 2.54 - 2.67 (2H, m), 3.85 (1H, t, J = 5.7 Hz), 3.94 (1H, t, J = 5.7 Hz), 4, 28 (1H, d, J = 2.7 Hz), 4.36 (1H, d, J = 2.7 Hz), 5.94 - 6.06 (1H, m), 7.16 - 7.21 (2H, m), 7.36-7.41 (2H, m).

Reference Example 318 4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine-1-carbonyl chloride [1738] a light brown oil, 60% yield [1739] ¹ H NMR (CDCb) δ ppm :

[1740] 2.54 - 2.67 (2H, m), 3.51 (1H, t, J = 5.6 Hz), 3.81 (3H, s), 3.92 - 4.02 (1H ,

m), 4.23 - 4.31 (1H, m), 4.31 - 4.37 (1H, m), 5.87 - 5.96 (1H, m), 6.85 - 6.90 ( 2H, m), 7.29-7.35 (2H, m).

Reference Example 319 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carbonyl chloride [1741] a light brown oil, 100% yield [1742] ¹ H NMR (CDCb) δ ppm :

[1743] 2.58-2.71 (2H, m), 3.87 (1H, t, J = 5.7 Hz), 3.96 (1H, t, J = 5.7 Hz), 4, 31 (1H, d, J = 2.8 Hz), 4.39 (1H, d, J = 2.8 Hz), 6.04 - 6.15 (1H, m), 7.45-7.63 (4H, m). Reference Example 320 4- (4-bromophenyl) -1,2,3,6-tetrahydropyridine-l-carbonyl chloride [1744] a light brown oil, 100% yield [1745] ¹ H NMR (CDCb) δ ppm :

[1746] 2.52 - 2.67 (2H, m), 3.84 (1H, t, J = 5.7 Hz), 3.93 (1H, t, J = 5.7 Hz), 4, 27 (1H, d, J = 2.6 Hz), 4.35 (1H, d, J = 2.6 Hz), 5.94 - 6.06 (1H, m), 7.21 - 7.24 (2H, m), 7.43-7.49 (2H, m).

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Reference Example 321 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine-l-carbonyl chloride [1747] a light brown oil, 100% yield [1748] ¹ H NMR (CDCb) δ ppm :

[1749] 2.54 - 2.67 (2H, m), 3.84 (1H, t, J = 5.7 Hz), 3.93 (1H, t, J = 5.7 Hz), 4, 27 (1H, d, J = 2.6 Hz), 4.35 (1H, d, J = 2.6 Hz), 5.90 - 6.00 (1H, m), 7.00 - 7.07 (2H, m), 7.24-7.35 (2H, m).

Reference Example 322 N- (4-chlorophenyl) -N-cyclohexylcarbamyl chloride [1750] a light yellow crystalline powder, 100% yield [1751] ¹ H NMR (CDCb) δ ppm:

[1752] 0.79 - 1.06 (1H, m), 1.14 (2H, t, J = 3.5 Hz, 12.5 Hz), 1.23 - 1.44 (2H, m),

1.50 -65 (1H, m), 1.67 - 1.81 (2H, m), 1.87 -2.00 (2H, m), 4.78 (1H, m), 7.06 - 7.10 (2H, m), 7.36-7.41 (2H, m).

Reference Example 323 N-methyl-N- (4-trifluoromethoxybenzyl) carbamyl chloride [1753] a yellow oil, 100% yield [1754] ¹ H NMR (CDCb) δ ppm:

[1755] 3.09 (3H, s), 4.58 (2H, s), 7.16 - 7.33 (4H, m).

Reference Example 324 4 - [(4-trifluoromethylbenzylidene) amino] piperazine-1-carbonyl chloride [1756] a brown oil, 100% yield [1757] ¹ H NMR (CDCb) δ ppm:

[1758] 3.17 - 3.39 (4H, m), 3.74 - 4.02 (4H, m), 7.56 (1H, s), 7.60 (2H, d, J = 8, 3

Hz), 7.69 (2H, d, J = 8.3 Hz).

Reference Example 325

Preparation of 4- (4-trifluoromethoxyphenyl) piperazine-1-carbonyl [1759] A mixture of 1- (4-trifluoromethoxyphenyl) piperazine (1.0 g, 4.1 mmol), triphosgene (0.42 g, 1 , 4 mmol), and pyridine (0.66 ml, 8.2 mmol) in toluene (20 ml) was stirred at 100 ° C for 4.5 hours. To this was added ethyl acetate, and the mixture was

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[1760] ¹ H NMR (CDCb) δ ppm:

[1761] 3.08 - 3.30 (4H, m), 3.67 -4.00 (4H, m), 6.79-6.98 (2H, m), 7.08 - 7.17 ( 2H,

m).

[1762] Using corresponding starting materials, quantitatively compounds of Reference Examples 326 to 332 were prepared in the same manner as described in Reference Example 325.

Reference Example 326 4- (4-trifluoromethylphenyl) piperazine-1-carbonyl chloride [1763] ¹ H NMR (CDCb) δ ppm:

[1764] 3.26 - 3.39 (4H, m), 3.76 - 3.87 (2H, m), 3.87 - 3.98 (2H, m), 6.87 - 6.98 ( 2H,

m), 7.48-7.59 (2H, m).

Reference Example 327 4- (4-methoxyphenyl) piperazine-1-carbonyl chloride [1765] ¹ H NMR (CDCb) δ ppm:

[1766] 3.04 - 3.15 (4H, m), 3.52 - 3.75 (2H, m), 3.75 - 3.92 (2H, m), 3.78 (3H, s) ,

6.81 -6.98 (4H, m).

Reference Example 328 4- (4-chlorophenyl) piperazine-1-carbonyl chloride [1767] ¹ H NMR (CDCb) δ ppm:

[1768] 3.10-3.25 (4H, m), 3.37 - 3.52 (2H, m), 3.73 - 3.90 (2H, m), 6.83 - 6.88 ( 2H,

m), 7.20-7.25 (2H, m).

Reference Example 329 4- (3-chlorophenyl) piperazine-1-carbonyl chloride [1769] ¹ H NMR (CDCb) δ ppm:

[1770] 3.15-3.29 (4H, m), 3.73 - 3.94 (4H, m), 6.77-6.81 (1H, m), 6.88-6.91 ( 2H,

m), 7.20 (1H, t, J = 8.3 Hz).

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Reference Example 330 4- (3,4-dichlorophenyl) piperazine-1-carbonyl chloride [1771] ¹ H NMR (CDCl3) δ ppm:

[1772] 3.08 - 3.27 (4H, m), 3.37 - 3.48 (2H, m), 3.60 - 3.73 (1H, m), 3.73 - 3.90 ( 1H,

m), 6.75 (1H, dd, J = 2.9 Hz, 9.0 Hz), 6.96 - 6.98 (1H, m), 7.30 (1H, dd, J = 5.1 Hz, 9.0 Hz).

Reference Example 331 4- (4-fluorophenyl) piperazine-1-carbonyl chloride [1773] ¹ H NMR (CDCb) δ ppm:

[1774] 3.04 - 3.19 (4H, m), 3.40 - 3.50 (2H, m), 3.62-3.75 (1H, m), 3.75 - 3.92 ( 1H,

m), 6.86-7.03 (4H, m).

Reference Example 332 4- (3-trifluoromethylphenyl) piperazine-1-carbonyl chloride [1775] ¹ H NMR (CDCb) δ ppm:

[1776] 3.21 -3.35 (4H, m), 3.42 - 3.54 (2H, m), 3.77-3.96 (2H, m), 7.02 - 7.19 ( 3H,

m), 7.31 -7.46 (1H, m).

Reference Example 333

Preparation of tert-butyl 4- [1 - (4-trifluoromethoxyphenyl) pipendin-4-yl] piperazine-1-carboxylate [1777] A mixture of ter-butyl 4-piperidin-4-ylpiperazine-1-carboxylate (1.5 g, 5.67 mmol), 4- (trifluoromethoxy) bromobenzene (3.36 g, 13.92 mmol), palladium acetate (25 mg, 0.11 mmol), BINAP (87 mg, 0.14 mmol), and have -sodium butoxide (1.07 g, 11.14 mmol) in toluene (20 ml) was stirred at 80 ° C under a nitrogen atmosphere for 8 hours. The reaction mixture was allowed to return to room temperature, to which ethyl acetate (10 ml) and brine (20 ml) were added, and the mixture was filtered. The organic layer was separated, and dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving 4- [1- (4-trifluoromethoxyphenyl) pipendin-4il] piperazine-1 tert-butyl carboxylate (1.01 g, 42%) as a yellow powder.

[1778] ¹ H NMR (CDCb) δ ppm [1779] 1.49 (9H, s), 1.52-1.75 (2H, m), 1.83-1.99 (2H, m), 2 , 31-2.52 (5H, m), 2.64

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2.81 (2H, m), 3.36-3.49 (4H, m), 3.62-3.75 (2H, m), 6.86 (2H, d, J = 8.5 Hz) , 7.09 (2H, d, J = 8.5 Hz).

Reference Example 334

Preparation of terbutyl 1 - [1 - (4-trifluoromethoxyphenyl) piperidin-4-yl] piperazine [1780] 4- [1- (4-trifluoromethoxyphenyl) piperidin-4-yl] piperazine-1-carboxylate (1 g, 2 , 33 mmol) was dissolved in methylene chloride (10 ml), to which trifluoroacetic acid (10 ml) was added while cooling in an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with 25% aqueous sodium hydroxide solution (40 ml) and brine (10 ml), and dried over sodium sulfate. After filtration, the filtrate was concentrated giving 1- [1- (4trifluoromethoxyphenyl) piperidin-4-yl] piperazine (770 mg, quantitative) as a yellow amorphous form.

[1781] ¹ H NMR (CDCb) δ ppm [1782] 1.52-1.75 (2H, m), 1.83-1.99 (2H, m), 2.25-2.38 (1 H , m), 2.48-2.76 (6H, m),

2.79-2.99 (4H, m), 3.56-3.75 (2H, m), 6.89 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz).

[1783] The compounds were prepared in the same manner as described in Reference Example 334.

Table 1

Reference Example X R ¹ H NMR (CDCb) δ ppm 335 none OCF3 1.52-1.75 (2H, m), 1.83-1.99 (2H, m), 2.25-2.35 (1H, m), 2,482.76 (6H, m), 2, 79-2.99 (4H, m), 3.56-3.75 (2H, m), 6.89 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz) 336 C = O Cl 1.31-1.55 (2H, m), 1.69-1.98 (2H, m), 2.36-2.60 (5H, m), 2.693.00 (6H, m), 3, 69-3.86 (1 H, m), 4.55-4.79 (1 H, m), 7,247.43 (4H, m) 337 C = O OCF3 1.31 - 1.60 (2H, m), 1.71 - 2.00 (2H, m), 2.38 - 2.60 (5H, m), 2.67 - 3.07 (6H, m), 3.62-3.86 (1 H, m), 4.57-4.83 (1 H, m), 7.25 (2H, d, J = 2.3Hz , 8.7Hz), 7.45 (2H, d, J = 2.3Hz, 8.7Hz). 338 ch ₂ Cl 1.45-1.60 (2H, m), 1.67-1.83 (2H, m), 1.86-2.00 (2H, m), 2.12- 2.24 (1 H, m), 2.45-2.57 (4H, m), 2.79-2.93 (6H, m), 3.44 (2H, s), 7.14-7.31 (4H, m) 339 ch ₂ OCF3 1.48-1.81 (4H, m), 1.85-2.00 (2H, m), 2.12-2.29 (1 H, m), 2.43-

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2.57 (4H, m), 2.76-2.98 (6H, m), 3.46 (2H, s), 7.15 (2H, d, J = 8.5 Hz), 7.33 (2H, d, J = 8.5 Hz)

Table 2

Reference Example X R ¹ H NMR (CDCb) δ ppm 340 C = O Cl 1.29-1.48 (2H, m), 1.67-1.86 (2H, m), 2.31-2.69 (7H, m), 3.07-3.21 (2H, m ), 3.31-3.50 (2H, m), 3.60-3.83 (2H, m), 7.26-7.45 (4H, m) 341 C = O OCF3 1.31-1.50 (2H, m), 1.64-1.83 (2H, m), 2.29-2.69 (7H, m), 3.07-3.21 (2H, m), 3.31-3.50 (2H, m), 3.64-3.83 (2H, m), 7.25 (2H, d, J = 8 , 7Hz), 7.45 (2H, d, J = 8.7Hz) 342 ch ₂ OCF3 1.25-1.48 (2H, m), 1.69-1.86 (2H, m), 2.19-2.62 (11H, m), 3.00-3.17 (2H, m ), 3.50 (2H, s), 7.15 (2H, d, J = 8.6Hz), 7.34 (2H, d, J = 8.6Hz) 343 ch ₂ Cl 1.24-1.43 (2H, m), 1.74-1.86 (2H, m), 2.21-2.60 (11H, m), 3.02-3.17 (2H, m ), 3.46 (2H, s), 7.19-7.33 (4H, m) 344 none OCF3 1.31-1.51 (2H, m), 1.76-1.93 (2H, m), 2.29-2.45 (1H, m), 2.52-2.79 (6H, m ), 3.10-3.26 (6H, m), 6.88 (2H, d, J = 8.6Hz), 7.10 (2H, d, J = 8.6Hz). 345 none Cl 1.33-1.52 (2H, m), 1.81-1.98 (2H, m), 2.26-2.43 (1H, m), 2.52-2.74 (6H, m), 3.05-3.21 (6H, m), 6.84 (2H, d, J = 6.9Hz), 7.19 (2H, d, J = 6.9Hz)

Table 3

0 — R

Reference Example R ¹ H NMR (CDCb) δ ppm 346 4-CIPh- 2.98-3.12 (8H, m), 6.80-6.94 (6H, m), 7.24 (2H, d, J = 2.3Hz, 6.8Hz) 347 4-CF ₃ PhCH ₂ - 3.04 (8H, s), 5.08 (2H, s), 6.90 (4H, s), 7.54 (2H, d, J = 8.2Hz), 7.63 (2H, d, J = 8.2Hz) 348 4-CIPhCH ₂ - 3.03 (8H, s), 4.98 (2H, s), 6.89 (4H, s), 7.35 (4H, s). 349 4-CF ₃ OPhCH ₂ - 3.04 (8H, s), 5.01 (2H, s), 6.90 (4H, s), 7.22 (2H, d, J = 8.5 Hz), 7.45 (2H, d, J = 8.5 Hz) 350 4-CF ₃ OPh- 2.96-3.14 (8H, m), 6.82-6.98 (6H, m), 7.06-7.16 (2H, m) 351 4-CF ₃ Ph- 2.96-3.14 (8H, m), 6.84-7.00 (6H, m), 7.53 (2H, d, J = 8.6Hz)

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Table 4

Reference Example R ¹ H NMR (CDCb) δ ppm 352 Cl- 2.96-3.16 (8H, m), 3.97 (1 H, br), 4.20 (1 H, d, J = 5.4 Hz), 6.55 (1 H, d, J = 8.8 Hz), 6.60 (1 H, d, J = 8.8 Hz), 6.90 (1 H, d, J = 8.8 Hz), 7.00-7.14 (4H, m), 7.18-7.25 (1 H, m) 353 CF3O- 2.94-3.20 (8H, m), 4.00 (1 H, br), 4.21 (1H, d, J = 5.3Hz), 6.57 (1 H, d, J = 6 , 8Hz), 6.64 (1H, d, J = 8.8Hz), 6.80-7.12 (5H, m), 7.16-7.25 (1H, m)

Table 5

Reference Example R ¹ H NMR (CDCb) δ ppm 354 1.51-1.73 (2H, m), 1.76-1, 92 (2H, m), 2.51- 2.82 (3H, m), 3.10-3.27 (2H, m), 6.92-7.08 (4H, m), 7.12-7.27 (2H, m), 7, 56 (2H, d, J = 8.6 Hz) 355 1.33-1.60 (4H, m), 1.69-2.02 (4H, m), 2,292.64 (5H, m), 2.76-2.88 (2H, m), 3, 05-3.17 (2H, m), 4.14-4.31 (1H, m), 6.85 (2H, d, J = 8.7Hz), 7.12 (2H, d, J = 8 , 7Hz) 356 0 - (\ /) OCF, Η V // 1.52-1.98 (4H, m), 2.26-2.43 (1H, m), 2,552.74 (2H, m), 3.10-3.26 (2H, m), 7 , 18 (2H, d, J = 8.4Hz), 7.55 (2H, d, J = 8.4Hz) 357 0 ^to O ^ C ^ ^ocf3 1.60-1.81 (4H, m), 2.57-2.74 (3H, m), 3.05- 3.21 (6H, m), 3.60-3.83 (4H, m), 6.90 (2H, d, J = 8.4Hz), 7.13 (2H, d, J = 8.4Hz ) 358 1.56-1.73 (2H, m), 1.83-1.89 (3H, m), 2.572.82 (3H, m), 3.18-3.24 (2H, m), 6, 95-7.05 (4H, m), 7.20-7.25 (2H, m), 7.53-7.57 (2H, m) 359 - ^0CF3 1.57-1.86 (4H, m), 2.52-2.81 (4H, m), 3.19- 3.25 (2H, m), 5.03 (2H, s), 6.89-6.94 (2H, m), 7.11-7.25 (4H, m), 7.44-7, 48 (2H, m) 360 1.51-1.68 (3H, m), 1.78-1.84 (2H, m), 2,502.64 (1 H, m), 2.67-2.79 (2H, m), 3 , 15-3.21 (2H, m), 5.11 (1H, s), 6.87-6.94 (2H, m), 7,127.18 (2H, m), 7.52-7.57 (2H, m), 7.62-7.66 (2H, m) 361 - 1.60-2.12 (5H, m), 2.52-2.66 (1 H, m), 2.712.83 (2H, m), 3.22-3.28 (2H, m), 5 , 01 (2H, s), 6.88-6.93 (2H, m), 7.11-7.18 (2H, m), 7.30-

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7.41 (4H, m) 362 ch ₃ 1.86-2.18 (3H, m), 2.35-2.52 (1 H, m), 2,612.69 (1 H, m), 2.93-3.01 (5H, m), 3.24-3.59 (3H, m), 4.49 (2H, s), 6.67-6.70 (2H, m), 7,077.17 (4H, m), 7.23-7, 27 (2H, m)

Table 6

Reference Example R1 R2 ¹ H NMR (CDCb) δ ppm 363 0 CH ₃ I J < ^CHí —N N'V'UH ₃ CH ₃ 1.50 (9H, s), 2.44 (3H, s), 3.00-3.14 (4H ,, m), 3.49-3.57 (4H, m), 3.72 (2H , s), 6.89 (2H, d, J = 7.2 Hz), 7.26 (2H, d, J = 7.2 Hz). 364 0 CH ₃ I J < ^CHí —N N'v'UH ₃ C2H5 1.15 (3H, t, J = 7.1 Hz), 1.48 (9H, s), 2.18 (1 H, brs), 2.69 (2H, q, J = 7.1 Hz), 3.09-3.12 (4H, m), 3.55-3.59 (4H, m), 3.73 (2H, s), 6.866.92 (2H, m), 7.23-7, 26 (2H, m). 365 ^ ch, / \ / N \ / ⁼ \ - ^N / // - ^Cl CH3 1.09-1.16 (3H, m), 1.78-1.88 (2H, m), 2.49 (3H, s), 2.73-2.80 (2H, m), 3.173, 31 (3H, m), 3.62-3.79 (5H, m), 3.92 (2H, s), 6.67-6.70 (2H, m), 6.91-6.93 ( 2H, m), 7,137.19 (2H, m), 7.39-7.42 (2H, m).

Table 7

Reference Example R ¹ H NMR (CDCb) δ ppm 366 -Cl 1.51-1.67 (2H, m), 1.90-2.04 (2H, m), 2.72 (2H, s), 3.18-3.43 (4H, m), 6, 89 (2H, d, J = 8.4Hz), 7.21 (2H, d, J = 8.4Hz) 367 -OCF ₃ 1.53-1.67 (2H, m), 1.86-2.04 (2H, m), 2.73 (2H, s), 3.22-3.45 (4H, m), 6, 93 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.4 Hz). 368 ch ₃ /// ocf ₃ 1.53-1.63 (2H, m), 1.90-2.06 (2H, m), 2.73 (2H, s), 3.24 (3H, s), 3.27-3, 45 (4H, m), 6.72 (2H, d, J = 8.4 Hz), 6.90-7.10 (6H, m). 369 ✓ikO 1.54-1.69 (2H, m), 1.92-2.06 (2H, m), 2.73 (2H, s), 3.20-3.43 (4H, m), 6, 84-6.96 (6H, m), 7.14 (2H, d, J = 8.4Hz)

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370 - ⁿ X3 ^{/ 0} ' ^x ' ^^ ° ^cf 3 1.58-1.69 (2H, m), 1.88-2.15 (6H, m), 2.71 (2H, s), 2.90-3.04 (2H, m), 3, 17-3.44 (6H, m), 4.31-4.46 (1 H, m), 6.85-6.94 (6H, m), 7.14 (2H, d, J = 8, 4Hz) 371 - ^N \ / ^N -XX- ^0CF 3 1.55-1.71 (2H, m), 1.92-2.04 (2H, m), 2.72 (2H, s), 3.12-3.35 (12H, m), 6, 86-7.00 (6H, m), 7.14 (2H, d, J = 8.5 Hz).

[1784] The following compounds were prepared in the same manner as described in Reference Example 186.

Reference Example 372

- (4-hydroxyphenyl) -4-phenylpiperidin-4-ol [1785] Mass Spectrum: 269 (M ⁺ )

Reference Example 373

4- (4-chlorophenyl) -1 - (4-hydroxyphenyl) piperidin-4-ol [1786] Mass Spectrum: 349 (M ⁺ -1)

Reference Example 374

1- (4-hydroxyphenyl) -4- (4-trifluoromethoxyphenyl) pipendin-4-ol [1787] Mass Spectrum: 353 (M ⁺ )

Reference Example 375 (4-hydroxyphenyl) - [4- (4-trifluoromethoxyphenoxy) piperidin-1-yl] methanone [1788] Mass Spectrum: 381 (M ⁺ )

Reference Example 376

Tert-butyl 1- (4-hydroxyphenyl) piperidine-4-carboxylate [1789] ¹ H NMR (CDCb) δ ppm 1.46 (91-1, s), 1.76-2.05 (4H, m) , 2.23-2.34 (1 H, m), 2.62-2.73 (2H, m), 3.39-3.48 (2H, m), 4.39-4.49 (1 H, m), 4.78 (1 H, s), 6.72-6.78 (2H, m), 6.82-6.89 (2H, m).

Reference Example 377

4- (4-phen i Ipiperid in-1-yl) phenol [1790] Mass Spectrum: 253 (M ⁺ )

Reference Example 378

4- (4,4-dietoxypiperidin-1-yl) phenol [1791] Mass Spectrum: 265 (M ⁺ )

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Reference Example 379

2-dimethylaminomethyl-4- [4- (4-trifluoromethoxyphenoxy) pipendin-1-yl] phenol [1792] Mass Spectrum: 410 (M ⁺ )

Reference Example 380

4- (4- [1,3] dioxolan-2-ylpiperidin-1-yl) phenol [1793] ¹ H NMR (CDCb) δ ppm 1,51-1,70 (21-1, m), 1.80 -1.92 (2H, m), 2.53-2.66 (2H, m), 3.48-3.57 (2H, m), 3.84-3.92 (2H, m), 3 , 92-4.02 (2H, m), 4.63 (1 H, brs), 4.69 (1 H, d, J = 4.9 Hz), 6.70-6.78 (2H, m ), 6.83-6.91 (2H, m).

Reference Example 381

4- [4- (4-trifluoromethoxyphenyl) piperazin-1-yl] phenol [1794] Mass Spectrum: 337 (M ⁺ )

Reference Example 382

Tert-butyl 4- (4-hydroxyphenoxy) piperidine-1-carboxylate [1795] Mass Spectrum: 293 (M ⁺ )

Reference Example 383

4- [1 - (4-trifluoromethylphenyl) piperidin-4-yloxy] phenol [1796] Mass Spectrum: 337 (M ⁺ )

Reference Example 384

4- (1,4-dioxa-8-azospiro [4,5] decan-8-yl) phenol [1797] ¹ H NMR (CDCb) δ ppm 1.87 (4H, t, J = 5.7 Hz) , 3.18 (4H, t, J = 5.7 Hz), 3.99 (4H, s), 6.74 (2H, d, J = 8.9 Hz), 6.88 (2H, d, J = 8.9 Hz).

Reference Example 385

4- (4-phen i 1-1,2,3,6-tetrahydropyrid in-1-yl) phenol [1798] Mass Spectrum: 251 (M ⁺ )

Reference Example 386

Tert-butyl 4- (4-hydroxyphenyl) piperazine-1-carboxylate [1799] ¹ H NMR (CDCb) δ ppm 1.49 (9H, s), 2.95-3.00 (4H, m), 3 , 55-3.60 (4H, m), 5.77 (1H, s), 6.74-6.86 (4H, m).

Reference Example 387

4- [4- (4-trifluoromethoxyphenyl) piperazin-1-yl] phenol

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511/854 [1800] ¹ H NMR (CDCb) δ ppm 3.19-3.24 (41-1, m), 3.29-3.34 (4H, m), 4.51 (1 H, s ),

6.76- 6.82 (2H, m), 6.87-6.97 (4H, m), 7.11-7.16 (2H, m).

Reference Example 388

4- {4 - [(4-trifluoromethoxybenzylidene) amino] piperazin-1-yl} phenol [1801] Mass Spectrum: 349 (M ⁺ -1)

Reference Example 389

4- [4- (4-chlorobenzyl) piperazin-1-yl] phenol [1802] ¹ H NMR (CDCb) δ ppm 2.60 (4H, t, J = 4.8 Hz), 3.08 (4H, t, J = 4.8 Hz), 3.53 (2H, s), 6.71-6.78 (2H, m), 6.81-6.89 (2H, m), 7.27-7 , 42 (4H, m).

Reference Example 390

3- (4-hydroxyphenyl) oxazolidin-2-one [1803] ¹ H NMR (CDCb) δ ppm 3.94-4.01 (2H, m), 4.35-4.42 (2H, m), 6 , 73-6.80 (2H, m), 7.29-7.36 (2H, m), 9.34 (1 H, s).

Reference Example 391

4- (4-pyridyl) phenol [1804] ¹ H NMR (CDCb) δ ppm 6.87-6.93 (2H, m), 7.60-7.70 (4H, m), 8.54-8 , 57 (2H, m), 9.85 (1 H, s).

Reference Example 392

4-hydroxy-N- (4-trifluoromethoxyphenyl) benzamide [1805] ¹ H NMR (CDCb) δ ppm 6.84-6.87 (2H, m), 7.31-7.34 (2H, m), 7 , 83-7.87 (4H, m), 10.11 (1H, brs), 10.15 (1 H, brs).

Reference Example 393 (4-hydroxyphenyl) - (4-fluoromethoxyphenyl) methanone [1806] ¹ H NMR (CDCb) δ ppm 6.08 (1 H, s), 6.92-6.96 (2H, m), 7.30-7.33 (2H, m),

7.76- 7.83 (4H, m).

Reference Example 394 (4-hydroxyphenyl) - (4-fluoromethylphenyl) methanone [1807] Mass Spectrum: 266 (M ⁺ )

Reference Example 395

4- (4-trifluoromethoxyphenoxy) phenol

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7.13-7.16 (21-1, m).

Table 8

Reference Example R1 NMR or Esp. Pasta 396 4-CIPh- ¹ H NMR (CDCb) δ 1.87-2.01 (2H, m), 2.04-2.16 (2H, m), 2,913.02 (2H, m), 3.29-3.39 ( 2H, m), 4.34-4.44 (1 H, m), 4.85 (1 H, s), 6.71-6.78 (21-1, m), 6.82-6, 92 (4H, m), 7.20-7.26 (2H, m). 397 4-CF ₃ Ph- ¹ H NMR (CDCb) δ 1.90-2.05 (2H, m), 2.08-2.20 (2H, m), 2,943.05 (2H, m), 3.30-3.40 ( 2H, m), 4.46-4.56 (1 H, m), 4.64 (1 H, s), 6.72-6.80 (2H, m), 6.86-6.93 ( 2H, m), 6.96-7.00 (2H, m), 7,527.56 (2H, m). 398 4-FPh- ¹ H NMR (CDCb) δ 1.86-2.00 (2H, m), 2.04-2.16 (2H, m), 2.903.00 (2H, m), 3.30-3.40 ( 2H, m), 4.29-4.39 (1 H, m), 4.72 (1 H, s), 6.71-6.78 (21-1, m), 6.83-7, 01 (6H, m). 399 4-CH ₃ OPh- ¹ H NMR (CDCb) δ 1.86-2.00 (2H, m), 2.05-2.13 (2H, m), 2,882.99 (2H, m), 3.31-3.41 ( 2H, m), 3.77 (3H, s), 4.25-4.35 (1 H, m), 4.72 (1 H, s), 6.72-6.77 (2H, m) , 6.80-6.92 (6H, m). 400 4-CH ₃ Ph- ¹ H NMR (CDCb) δ 1.87-2.01 (2H, m), 2.04-2.16 (2H, m), 2.29 (3H, s), 2.90-3.00 ( 2H, m), 3.30-3.40 (2H, m), 4.33-4.43 (1 H, m), 4.85 (1 H, s), 6.71-6.78 ( 2H, m), 6.80-6.92 (4H, m), 7.067.10 (21-1, m). 401 -ΟθΗδ ¹ H NMR (CDCb) δ 1.89-2.03 (2H, m), 2.04-2.18 (2H, m), 2,923.02 (2H, m), 3.31-3.41 ( 2H, m), 4.39-4.49 (1 H, m), 4.92 (1 H, s), 6.70-6.78 (2H, m), 6.84-6.98 ( 5H, m), 7.24-7.33 (2H, m). 402 4-CNPh- ¹ H NMR (CDCb) δ 1.90-2.04 (2H, m), 2.09-2.18 (2H, m), 2.94-3.04 (2H, m), 3.29- 3.39 (2H, m), 4.49-4.55 (1 H, m), 6.75- 6.80 (2H, m), 6.86-6.90 (2H, m), 6 , 93-7.00 (2H, m), 7,557.62 (2H, m). 403 -CFh-cycle-CeHn Ms: 289 (M +) 404 ¹ H NMR (CDCb) δ 1.54-2.07 (11 H, m), 2.74-2.87 (2H, m), 3,313.43 (2H, m), 3.47-3.57 (1 H, m), 3.72-3.83 (1 H, m), 3,883.98 (1 H, m), 4.74-4.78 (1 H, m), 6.69-6 , 76 (2H, m), 6,836.88 (2H, m).

Table 9

R1

Example Reference deR1 R2 NMR 405 -CH ₃ 4-CF ₃ OPh- ¹ H NMR (CDCb) δ 3.23 (3H, s), 4.88 (1 H, s), 6.66-

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6.73 (2H, m), 6.80-6.87 (2H, m), 6.99-7.08 (4H, m).

406 -CH ₃ 4-CIPh- ¹ H NMR (CDCI ₃ ) δ 3.22 (3H, s), 4.69 (1 H, brs), 407 -CH ₃ 4-CF ₃ Ph- 6.66-6.68 (2H, m), 6.81-6.84 (2H, m), 7.017.04 (2H, m), 7.10-7.13 (2H, m). ¹ H NMR (CDCI ₃ ) δ 3.28 (3H, s), 4.80 (1 H, brs), 408 -C2H5 4-CF ₃ OPh- 6.68-6.71 (2H, m), 6.85-6.88 (2H, m), 7.067.09 (2H, m), 7.37-7.40 (2H, m). ¹ H NMR (CDCb) δ 1.19 (3H, t, J = 7.1 Hz), 3.66 (2H, 409 4-CF ₃ OPhCH ₂ - 4-CF ₃ OPhCH ₂ - q, J = 7.1 Hz), 4.75 (1 H, brs), 6.62-6.66 (2H, m), 6.83-6.87 (2H, m), 6.98-7 , 05 (4H, m). ¹ H NMR (CDCb) δ 4.34 (1 H, bs), 4.49 (4H, brs), 410 -C2H5 4-CF ₃ Ph- 6.61-6.72 (41-1, m), 7.14-7.16 (4H, m), 7,247.26 (4H, m). ¹ H NMR (CDCb) δ 1.21 (3H, t, J = 7.1 Hz), 3.70 (2H, 411 -C2H5 4-CIPh- q, J = 7.1 Hz), 4.87 (1 H, brs), 6.62-6.65 (2H, m), 6.85-6.91 (2H, m), 7.03-7 .09 (2H, m), 7,347.37 (2H, m). ¹ H NMR (CDCb) δ 1.17 (3H, t, J = 7.1 Hz), 3.65 (2H, 412 -CH ₃ 4-CF ₃ OPhCH ₂ - q, J = 7.1 Hz), 4.73 (1 H, brs), 6.59-6.63 (2H, m), 6.82-6.85 (2H, m), 6.98-7 , 03 (2H, m), 7,067.10 (21-1, m). ¹ H NMR (CDCb) δ 2.90 (3H, s), 4.33 (1 H, brs), 413 -CH ₃ 4-CIPhCH ₂ - 4.40 (2H, brs), 6.66-6.70 (2H, m), 6.72-6.76 (2H, m), 7.13-7.16 (2H, m), 7, 25-7.27 (2H, m). ¹ H NMR (CDCb) δ 2.88 (3H, s), 4.34 (1 H, brs), 414 -CH ₃ 4-CF ₃ PhCH ₂ - 4.36 (2H, brs), 6.65-6.69 (2H, m), 6.71-6.76 (2H, m), 7.15-7.18 (2H, m), 7, 25-7.28 (2H, m). ¹ H NMR (CDCb) δ 2.92 (3H, s), 4.35 (1 H, brs), 415 -C2H5 4-CF ₃ OPhCH ₂ - 4.46 (2H, brs), 6.65-6.68 (2H, m), 6.73-6.76 (2H, m), 7.34-7.37 (2H, m), 7, 55-7.58 (2H, m). ¹ H NMR (CDCb) δ 1.14 (31-1, t, J = 7.1 Hz), 4.12 (2H, 416 -C2H5 4-CF ₃ PhCH ₂ - q, J = 7.1 Hz), 4.28 (1 H, brs), 4.39 (2H, brs), 6.506.80 (4H, m), 7.13-7.15 (2H, m), 7.26-7.28 (2H, m). ¹ H NMR (CDCb) δ 1.16 (31-1, t, J = 7.0 Hz), 3.38 (2H, 417 -C2H5 4-CIPhCH ₂ - brs), 4.29 (1 H, brs), 4.45 (2H, brs), 6.61-6.70 (41-1, m), 7.35-7.38 (2H, m), 7.54-7.56 (2H, m). ¹ H NMR (CDCb) δ 1.14 (31-1, t, J = 7.0 Hz), 3.35 (2H, 418 -coch ₃ -CeHs brs), 4.28 (1 H, brs), 4.36 (2H, brs), 6.62-6.70 (4H, m), 7.17-7.19 (2H, m), 7, 25-7.28 (2H, m). ¹ H NMR (CDCb) δ 2.06 (3H, s), 6.27 (1 H, brs), 419 -coch ₃ 4-CIPh- 6.69-6.80 (2H, m), 7.08-7.33 (7H, m). ¹ H NMR (CDCb) δ 2.06 (3H, s), 6.50 (1 H, brs),

6.63-6.85 (2H, m), 7.05-7.08 (2H, m), 7,187.38 (4H, m).

Table 10

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R1

N.

R2

H / 0 R3 Reference Example R1 R2 R3 NMR 420 -CH ₃ 4-CF ₃ OPh- -F ¹ H NMR (CDCI ₃ ) δ 3.22 (3H, s), 5.02 (1 H, brs), 6.57-6.71 (41-1, m), 7.01 -7.14 ( 3H, m). 421 -CH ₃ 4-CIPh- -F ¹ H NMR (CDCI ₃ ) δ 3.20 (3H, s), 5.02 (1 H, brs), 6.54-6.70 (4H, m), 7.07-7.13 (3H, m). 422 -co ₂ ch ₃ -CeHs -H ¹ H NMR (CDCb) δ 3.75 (3H, s), 5.86 (1 H, brs), 6.69-6.72 (2H, m), 7.05-7.08 (2H, m ), 7,187.31 (5H, m). 423 -co ₂ ch ₃ 4-CIPh- -H ¹ H NMR (CDCb) δ 3.75 (3H, s), 5.52 (1 H, brs), 6.73-6.76 (2H, m), 7.04-7.07 (2H, m ), 7,167.18 (21-1, m), 7.26-7.29 (2H, m). 424 -coch ₃ 4-CF ₃ Ph- -H ¹ H NMR (CDCb) δ 2.08 (3H, s), 6.04 (1 H, brs), 6.83-6.86 (2H, m), 7.09-7.12 (2H, m ), 7,377.40 (2H, m), 7.56-7.59 (2H, m). 425 -coch ₃ 4-CF ₃ OPh- -H ¹ H NMR (CDCb) δ 2.07 (3H, s), 6.60-6.92 (3H, m), 6.98-7.30 (6H, m). 426 -CH ₃ -CeHs -H ¹ H NMR (CDCb) δ 3.24 (3H, s), 4.63 (1 H, brs), 6.76-6.84 (5H, m), 7.01-7.05 (2H, m ), 7,177.22 (2H, m). 427 -coch ₃ 4-CIPh- -F ¹ H NMR (CDCb) δ 2.07 (3H, brs), 6.46-6.61 (2H, m), 6.96-7.36 (6H, m). 428 -coch ₃ 4-CF ₃ OPh- -F ¹ H NMR (CDCb) δ 2.07 (3H, brs), 6.48-6.62 (2H, m), 6.90-7.42 (6H, m).

Table 11

Reference Example R1 R2 NMR or Esp. Pasta 429 -Cebb 4-CF ₃ OPhCH ₂ - ¹ H NMR (CDCb) δ 4.72 (1 H, brs), 4.89 (2H, brs), 6,756.83 (5H, m), 7.05-7.18 (6H, m), 7, 34-7.37 (2H, m). 430 -CeHs 4-CF ₃ PhCH ₂ - ¹ H NMR (CDCb) δ 4.67 (1 H, brs), 4.95 (2H, brs), 6.746.83 (5H, m), 7.06-7.18 (4H, m), 7, 44-7.47 (2H, m), 7.54-7.57 (2H, m). 431 -CeHs 4-CIPhCH ₂ - ¹ H NMR (CDCb) δ 4.64 (1 H, brs), 4.86 (2H, brs), 6,746.82 (5H, m), 7.04-7.08 (2H, m), 7, 12-7.17 (2H, m), 7.26 (4H, brs).

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432 -COCH3 4-CF ₃ OPhCH ₂ - 433 -Cbb 4-CF ₃ PhCO- 434 -Cbb 4-CIPhCO- 435 -H 4-CF ₃ OPhCO- 436 -Cbb 4-CF ₃ OPhCO- 437 -Cbb 4-CF ₃ OPhO (CH ₂ ) ₃ - 438 -H ^N = \ - (\ z> —ci

¹ H NMR (CDCb) δ 1.89 (3H, s), 4.83 (2H, s), 6.54 (1 H, brs), 6.82 (4H, m), 7.09-7, 12 (21-1, m), 7.20-7.26 (2H, m).

¹ H NMR (CDCb) δ 3.46 (3H, s), 6.28 (1 H, brs), 6,686.71 (2H, m), 6.85-6.92 (2H, m), 7, 33-7.44 (4H, m).

¹ H NMR (CDCb) δ 3.44 (3H, s), 5.12 (1 H, brs), 6,676.72 (2H, m), 6.88-6.91 (2H, m), 7, 13-7.16 (2H, m), 7.21-7.24 (21-1, m).

¹ H NMR (CDCb) δ 6.71-6.76 (21-1, m), 7.48-7.52 (4H, m), 8.02-8.05 (2H, m), 9, 25 (1 H, s), 10.10 (1 H, brs).

¹ H NMR (CDCb) δ 3.45 (3H, s), 6.13 (1 H, brs), 6,696.72 (2H, m), 6.87-6.89 (2H, m), 6, 99-7.02 (2H, m), 7.31-7.34 (21-1, m).

¹ H NMR (CDCb) δ 1.97-2.06 (2H, m), 2.85 (3H, s), 3.42 (2H, t, J = 6.9Hz), 3.99 (2H, t, J = 6.0 Hz), 4.28 (1 H, brs), 6.65-6.75 (4H, m), 6.86-6.89 (2H, m), 7,117.14 (21 -1, m).

219 (M + -1)

Table 12

Reference example R1

439

440

441

442

NMR or Esp. Pasta

Ms: 367 (M +) ¹ H NMR (CDCb) δ 2.96 (3H, s), 4.43 (2H, brs), 4.68 (1 H, s), 6.63-6.66 (2H , m), 6.766.80 (2H, m), 7.05-7.08 (2H, m), 7.12-7.15 (2H, m).

¹ H NMR (CDCb) δ 1.90 (3H, brs), 4.83 (2H, s), 5.88 (1 H, brs), 6.74-6.76 (2H, m), 7.02 -7.06 (2H, m), 7.10-7.13 (2H, m), 7.60-7.63 (2H, m).

¹ H NMR (CDCb) õ

3.06 (3H, s), 4.52 (2H, s), 4.70 (1H, s), 6,716.81 (41-1, m), 7.05-7.07 (2H, m) , 7,417.44 (2H, m).

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443

444

445

446

447

¹ H NMR (CDCb) δ 2.99 (3H, s), 4.44 (2H, s), 4.68 (1 H, s), 6.66-6.70 (2H, m), 6.776, 81 (2H, m), 7.04-7.10 (4H, m).

¹ H NMR (CDCb) 03.95 (1 H, brs), 4.21 (2H, s), 4.69 (1 H, brs), 6.53-6.56 (2H, m), 6.796, 82 (2H, m), 7.09-7.12 (2H, m), 7.207.23 (2H, m).

¹ H NMR (CDCb) δ 4.28 (3H, brs), 4.71 (1H, brs), 6.60-6.63 (2H, m), 6.79-6.83 (2H, m), 7.217.23 (2H, m), 7.38-7.40 (2H, m).

¹ H NMR (CDCb) δ 2.16 (3H, s), 3.45 (2H, s), 3.48 (2H, s), 4.82 (1H, brs), 6,766.79 (2H, m ), 7.14-7.22 (4H, m), 7.35-7.38 (2H, m).

¹ H NMR (CDCb) δ 4.03 (1 H, brs), 4.22 (2H, s), 4.72 (1 H, brs), 6.56-6.69 (2H, m), 6.806 , 83 (2H, m), 7.01-7.04 (2H, m), 7,217.24 (2H, m).

Example 1

Preparation of 2-chloro-1 - (3-chloro-2-hydroxypropyl) -4-nitroimidazole [1809] Sodium hydrogen carbonate (1.25 g, 14.91 mmol) was added to a solution of 2-chloro-4 -nitro-1 H-imidazole (2 g, 13.56 mmol) and epichlorohydrin (1.38 g, 14.91 mmol) in acetonitrile (60 ml), and the resulting mixture was stirred at reflux for 4 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. Water (20 ml) was added to the residue, the resulting mixture was extracted with methylene chloride (15 ml) twice, and the extracts were dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / n-hexane = 1/1) giving 2-chloro-1- (3-chloro-2- hydroxypropyl) -4nitroimidazole (2.04 g, 63% yield) as a light yellow oil.

[1810] ¹ H NMR (CDCb) δ ppm:

[1811] 3.51 -3.70 (2H, m), 4.02-4.35 (4H, m), 7.92 (1H, s).

Example 2

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Preparation of 2-chloro-4-nitro-1- (oxiran-2-ylmethyl) imidazole [1812] 2-chloro-1- (3-chloro-2-hydroxypropyl) -4-nitroimidazole prepared in Example 1 (2.04 g, 8.5 mmol) was dissolved in methylene chloride (20 ml), and 1.8 diazabicyclo [5.4.0] -7-undecene (DBU) (2.04 ml, 13.67 mmol) was added the solution. The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with 3 N hydrochloric acid (20 ml) and a saturated saline solution (20 ml) in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving 2-chloro-4-nitro-1- (oxiran- 2-ylmethyl) imidazole (190 mg, 11% yield) as a colorless oil.

[1813] ¹ H NMR (CDCb) δ ppm:

[1814] 2.55 - 2.69 (1H, m), 2.97 (1H, t, J = 4.2 Hz), 3.26 - 3.43 (1H, m), 3.94 (1H , dd, J = 6.4 Hz, 15.0 Hz), 4.52 (1H, dd, J = 2.6 Hz, 15.0 Hz), 7.88 (1H, s).

Example 3

Preparation of 2-chloro-1 - (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole [1815] 2-chloro-4-nitro-1 H-imidazole (6.78 g, 46 mmol) and 4- 2-methyloxyran-2-ylmethyl nitrobenzoate (12 g, 51 mmol) were dissolved in ethyl acetate (24 ml), and triethylamine (1.3 ml, 9.2 mmol) was added to the solution. The resulting mixture was stirred at reflux for 14 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (40 ml) was added to the residue. The resulting precipitates were removed by filtration, and dissolved in methanol (120 ml). Potassium carbonate (318 mg, 2.3 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 1 hour. 6N hydrochloric acid (0.8 ml) and magnesium sulfate (8 g) were added to the resulting mixture in this order with cooling in an ice bath, and the resulting mixture was stirred for 30 minutes. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate (6 ml) and toluene (60 ml) were added to the residue. The resulting precipitates were removed by filtration and dried at 50 ° C giving 2-chloro-1- (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole (7.88 g,

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518/854 yield 72%) as a white powder.

[1816] ¹ H NMR (DMSO-de) δ ppm:

[1817] 1.02 (3H, s), 3.25 (2H, d, J = 5.3 Hz), 4.04 (2H, s), 4.98 (1H, s), 5.10 ( 1H, t,

J = 5.4 Hz), 8.29 (1H, s).

Example 4

Preparation of 2-chloro-1 - (2-hydroxy-3-methanesulfonyloxy-2-methylpropyl) -4-nitroimidazole [1818] Methanesulfonyl chloride (2.01 ml, 25.72 mmol) was added to a solution of 2 -chloro-1- (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole prepared in Example 3 (5.05 g, 21.43 mmol) in pyridine (10 ml) with cooling in an ice bath and the mixture The resulting mixture was stirred at room temperature for 1.5 hours. 6 N hydrochloric acid was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and then concentrated under reduced pressure to give 2-chloro-1- (2-hydroxy-3-methanesulfonyloxy-2-methylpropyl) -4nitroimidazole (6.72 g, quantitative) as a yellow oil.

[1819] ¹ H NMR (CDCb) δ ppm:

[1820] 1.31 (3H, s), 2.10 (1H, s), 3.11 (3H, s), 4.08 - 4.23 (4H, m), 8.02 (1H, s ).

Example 5

Preparation of 2-chloro-1- [2-hydroxy-2-methyl-3- (4-methylbenzenesulfonyloxy) propyl] -4nitroimidazole [1821] 2-chloro-4-nitro-1 H-imidazole (1 g, 6.78 mmol), 2-methyloxyran-2-ylmethyl paratoluenesulfonate (2.46 g, 10.15 mmol), benzyl (triethyl) ammonium chloride (1.50 mg, 0.66 mmol) and acetonitrile (10 ml) were stirred at reflux for 8 hours. The reaction mixture was allowed to return to room temperature, diluted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate twice, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 6/1) giving 2-chloro-1 - [2-hydroxy-2- methyl-3- (4-methylbenzenesulfonyloxy) propyl] -4nitroimidazole (1.86 g, 70% yield) as a light yellow oil.

[1822] ¹ H NMR (CDCb) δ ppm:

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519/854 [1823] 1.25 (3H, s), 2.46 (3H, s), 2.80 (1H, s), 3.91 (1H, d, J = 10.4 Hz), 3 , 95 (1H, d, J = 10.4 Hz), 4.04 - 4.16 (2H, m), 7.38 (2H, d, J = 8.0 Hz), 7.76 (2H, d, J = 8.0 Hz), 7.93 (1H, s).

Example 6

Preparation of 2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole [1824] 2-chloro-1- (2-hydroxy-3-methanesulfonyloxy-2-methylpropyl) -4-nitroimidazole prepared in the Example 4 (6.72 g, 21.43 mmol) was treated in the same manner as in Example 2 giving 2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole (5.6 g, yield of 94%) as a white powder.

[1825] ¹ H NMR (CDCb) δ ppm:

[1826] 1.39 (3H, s), 2.62 (2H, d, J = 4.0 Hz), 2.78 (1H, d, J = 4.0 Hz), 4.00 (1H, d,

J = 14.9 Hz), 4.38 (1H, d, J = 14.9 Hz), 7.87 (1H, s).

Example 7

Preparation of 2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitro-1 H-imidazole [1827] Using 2-chloro-1 - [2-hydroxy-2-methyl-3- (4- methylbenzenesulfonyloxy) propyl] 4-nitroimidazole prepared in Example 5 (1.11 g, 2.84 mmol) gave 2-chloro-1 - (2 methyloxyran-2-ylmethyl) -4-nitro-1 H-imidazole (523 mg, yield 85%) as a light yellow powder in the same way as in Example 2.

[1828] The properties of the compound obtained were the same as those of the compound obtained in Example 6.

Example 8

Preparation of (R) -2-chloro-1- [2-hydroxy-3- (4-methylbenzenesulfonyloxy) propyl] -4nitroimidazole [1829] 2-chloro-4-nitro-1 H-imidazole (10 g, 67.79 mmol) and (R) - (-) - glycidyl tosylate (17.02 g, 74.58 mmol) were dissolved in acetonitrile (50 ml), sodium hydrogen carbonate (6.26 g, 74.15 mmol) was added ) to the solution, and the resulting mixture was stirred at reflux for 3.5 hours. The reaction mixture was allowed to return to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / n-hexane = 1/2) giving (R) -2-chloro-1- [2-hydroxy-3- (4

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520/854 methylbenzenesulfonyloxy) propyl] -4-nitroimidazole (16.9 g, 66% yield) as a light yellow oil.

[1830] ¹ H NMR (CDCb) δ ppm:

[1831] 2.47 (3H, s), 3.65 (1H, d, J = 5.8 Hz), 3.93 - 4.33 (5H, m), 7.38 (2H, d, J =

8.3 Hz), 7.70 (2H, d, J = 8.3 Hz), 7.86 (1H, s).

Example 9

Preparation of (R) -2-chloro-4-nitro-1- (oxiran-2-ylmethyl) imidazole [1832] 2-chloro-4-nitro-1 H-imidazole (1 g, 6.78 mmol) and tosylate (R) - (-) - glycidyl (1.7 g, 7.45 mmol) were dissolved in tetrahydrofuran (THF) (10 ml), sodium hydrogen carbonate (600 mg, 7.14 mmol) was added to the solution , and the resulting mixture was stirred at reflux for 11 hours. The reaction mixture was concentrated under reduced pressure, water was added to the solution, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated saline solution in that order, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (ethyl acetate / n-hexane = 1/1) giving (R) -2-chloro-4-nitro-1- (oxiran -2-ylmethyl) imidazole (1.45 g, 57% yield) as a light yellow oil.

[1833] Optical purity 79.2% e.e.

[1834] [a] d ²⁷ = 42.55 ° (concentration: 1.262, CHCb) [1835] ¹ H NMR (CDCb) δ ppm:

[1836] 2.61 (1H, t, J = 2.5 Hz, 4.3 Hz), 2.97 (1H, t, J = 4.3 Hz), 3.25 - 3.34 (1H, m),

3.95 (1H, dd, J = 6.4 Hz, 15.0 Hz), 4.51 (1H, dd, J = 2.6 Hz, 15.0 Hz), 7.88 (1H, s) . Example 10

Preparation of (R) -2-chloro-1 - (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole [1837] 2-chloro-4-nitro-1 H-imidazole (600 g, 4.07 mol ) and (R) -2methyloxyran-2-ylmethyl 4-nitrobenzoate (1060 g, 4.47 mol) were dissolved in ethyl acetate (2124 ml), triethylamine (113.64 ml, 0.82 mol) was added to the solution, and the resulting mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (530 ml) and toluene (5300 ml) were added to the residue. The resulting precipitates were removed by filtration and dissolved in

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521/854 methanol (10.6 I). potassium carbonate disturbance (55.4 g, 0.4 mol) to the solution, the resulting mixture was stirred at room temperature for 1 hour, concentrated hydrochloric acid (66 ml) and magnesium sulfate (671 g) were added in that order with cooling in an ice bath, and the resulting mixture was stirred for 30 minutes. Insoluble materials were removed by means of filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (530 ml) and toluene (5300 ml) were added to the residue. The resulting precipitates were removed by filtration and dried at 50 ° C giving (R) -2-chloro-1- (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole (879.1 g, 92% yield) like a light brown powder.

[1838] Optical purity 99.0% e.e.

[1839] [a] d ²⁷ = 17.38 ° (concentration: 1.03, DMSO) [1840] ¹ H NMR (DMSO-de) δ ppm:

[1841] 1.01 (3H, s), 3.25 (2H, d, J = 5.3 Hz), 4.05 (2H, s), 5.01 (1H, s), 5.11 ( 1H, t,

J = 5.4 Hz), 8.32 (1H, s).

Example 11

Preparation of (R) -2-chloro-1 - (2-hydroxy-3-methanesulfonyloxy-2-methylpropyl) -4nitroimidazole [1842] (R) -2-chloro-1- (2,3-dihydroxy-2-methylpropyl ) -4-nitroimidazole prepared in Example 10 (879 g, 3.73 mol) was dissolved in pyridine (1778 ml) and cooled to 5 ° C. To this solution, methanesulfonyl chloride (432.7 ml,

5.59 mol) below 15 ° C, and the resulting mixture was stirred at the same temperature for 1 hour. 6 N hydrochloric acid (5500 ml) was added to the mixture below 30 ° C, and the resulting mixture was stirred for 40 minutes with cooling in an ice bath. The precipitates were removed by filtration and washed with water and toluene in that order giving primary crystals. In addition, the filtrate was extracted with ethyl acetate (5 liters) twice. The organic phase was washed with water, dried over magnesium sulfate, and filtered to give a solid. The filtrate was concentrated under reduced pressure. Toluene was added to the residue and the precipitates were removed by filtration giving a solid. The solids were combined and dried at 60 ° C giving (R) -2-chloro-1 - (2-hydroxy-3-methanesulfonyloxy-2-methylpropyl) -4-nitroimidazole (942.6 g,

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522/854 yield 81%) as a white powder.

[1843] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1844] 1.12 (3H, s), 3.23 (3H, s), 4.09 (2H, s), 4.13 (2H, s), 5.60 (1H, br), 8, 34 (1H,

s).

Example 12

Preparation of (R) -2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole [1845] (R) -2-chloro-1- (2-hydroxy-3-methanesulfonyloxy-2-methylpropyl ) -4-nitroimidazole prepared in Example 11 (942.6 g, 3 mol) was suspended in ethyl acetate (9426 ml). DBU (494 ml, 3.3 mol) was added to the suspension, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (5 liters). The water layer was extracted with ethyl acetate (5 liters) twice. The organic phases were combined, and the mixture was washed with a saturated saline solution (5 liters), dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / n-hexane = 1/2) giving (R) -2chloro-1- (2-methyloxyran- 2-ylmethyl) -4-nitroimidazole (600.7 g, 92% yield) as a white powder.

[1846] Optical purity 98.8% e.e.

[1847] [a] d ²⁶ = 31.11 ° (concentration: 2.02, CHCb) [1848] ¹ H NMR (CDCb) δ ppm:

[1849] 1.38 (3H, s), 2.62 (1H, d, J = 4.0 Hz), 2.78 (1H, d, J = 4.0 Hz), 4.00 (1H, d,

J = 14.9 Hz), 4.38 (1H, d, J = 14.9 Hz), 7.87 (1H, s).

Example 13

Preparation of (R) -2-chloro-1 - [2-hydroxy-2-methyl-3- (4-methylbenzenesulfonyloxy) propyl] -4nitroimidazole [1850] 2-chloro-4-nitro-1 H-imidazole (18, 4 g, 125 mmol) and (R) -2methyloxyran-2-ylmethyl sulfonate 4-methylbenzene (36.2 g, 149 mmol) were suspended in acetonitrile (150 ml). Benzyl (triethyl) ammonium chloride (5.7 g, 25 mmol) was added to the suspension, and the resulting mixture was stirred at reflux for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by means of

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523/854 column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving (R) -2-chloro-1- [2-hydroxy-2-methyl-3- (4-methylbenzenesulfonyloxy) propyl] -4nitroimidazole (20.1 g, 43%) as a white amorphous form.

[1851] ¹ H NMR (CDCb) δ ppm:

[1852] 1.24 (3H, s), 2.47 (3H, s), 2.81 (1H, s), 3.90 (1H, d, J = 10.4 Hz), 3.95 ( 1H, d, J = 10.4 Hz), 4.04 - 4.14 (2H, m), 7.39 (2H, d, J = 8.0 Hz), 7.76 (2H, d, J = 8.0 Hz), 7.91 (1H, s).

Example 14

Preparation of (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole (another method for synthesis of the compound of Example 12) [1853] 2-chloro-4-nitro-1 H- imidazole (1.51 g, 10.17 mmol) and (R) -2methyloxyran-2-ylmethyl 4-methylbenzene sulfonate (3.70 g, 15.25 mmol) were suspended in acetonitrile (150 ml). Benzyl (triethyl) ammonium chloride (0.23, 1.02 mmol) was added to this suspension, and the resulting mixture was stirred at reflux for 10 hours. After the reaction mixture was allowed to return to room temperature, ethyl acetate was added to the solution. The resulting mixture was washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and dissolved in ethyl acetate (40 ml). DBU (1.57 ml, 10.17 mmol) was added to the solution with ice bath cooling, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 7/3) giving (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole ( 1.50 g, 68% yield) as a light yellow oil.

Example 15

Preparation of (S) -2-chloro-4-nitro-1 - [2-hydroxy-3- (4-nitrobenzoyloxy) -2methylpropyl] imidazole [1854] 2-chloro-4-nitro-1 H-imidazole (3 g , 20.34 mmol) and (S) -2methyloxyran-2-ylmethyl 4-nitrobenzoate (5.31 g, 22.37 mmol) were dissolved in ethyl acetate (10

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524/854 ml). Triethylamine (0.57 ml, 4.07 mmol) was added to the solution, and the resulting mixture was stirred at 60-65 ° C for 10 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (3 ml) and toluene (30 ml) were added to the residue, and the resulting precipitates were removed by filtration giving (S) -2-chloro-4-nitro-1 [2-hydroxy-3- (4 -nitrobenzoyloxy) -2-methylpropyl] imidazole (6.82 g, 87% yield) as a yellow powder.

[1855] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1856] 1.23 (3H, s), 4.11 - 4.33 (4H, m), 5.61 (1H, s), 8, 25 (2H, d, J = 8.9 Hz), 8.31

-8.45 (3H, m).

Example 16

Preparation of (S) -2-chloro-1 - (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole [1857] (S) -2-chloro-4-nitro-1- [2-hydroxy-3 - (4-nitrobenzoyloxy) -2-methylpropyl] imidazole prepared in Example 15 (6.8 g, 17.67 mmol) was dissolved in methanol (68 ml). Potassium carbonate (122 mg, 0.88 mmol) was added to the solution, and the resulting mixture was stirred at room temperature overnight. The mixture was cooled in an ice bath, and 6 N hydrochloric acid (0.3 ml) and magnesium sulfate (3 g) were added to the mixture in that order, and the mixture was stirred for 30 minutes. Insoluble materials were removed by means of filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (3.4 ml) and toluene (34 ml) were added to the residue, and the resulting precipitates were removed by filtration giving (S) -2-chloro1 - (2,3-dihydroxy-2-methylpropyl) - 4-nitroimidazole (4.09 g, 97% yield) as a yellow powder.

[1858] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1859] 1.02 (3H, s), 3.25 (2H, d, J = 5.3 Hz), 4.05 (2H, s), 4.98 (1H, s), 5.11 ( 1H, t,

J = 5.2 Hz), 8.30 (1H, s).

Example 17

Preparation of (S) -2-chloro-1 - (2-hydroxy-2-methyl-3-methanesulfonyloxypropyl) -4nitroimidazole [1860] (S) -2-chloro-1- (2,3-dihydroxy-2-methylpropyl ) -4-nitroimidazole prepared in Example 16 (4.05 g, 16.9 mmol) was dissolved in pyridine (8 ml), and this solution was

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525/854 cooled to 4 ° C. Methanesulfonyl chloride (1.6 ml, 20.28 mmol) was added dropwise to the solution below 15 ° C followed by stirring at the same temperature for 1 hour. 6 N hydrochloric acid (33 ml) was added to the mixture below 30 ° C. The reaction mixture was extracted with methylene chloride (20 ml) three times. The organic phases were combined, washing with water (20 ml) and a saturated saline solution (20 ml), drying over sodium sulfate and then filtering. The filtrate was concentrated under reduced pressure. Toluene (10 ml) was added to the residue, and the resulting precipitates were removed by filtration giving (S) -2-chloro-1- (2-hydroxy2-methyl-3-methanesulfonyloxypropyl) -4-nitroimidazole (3.04g, 57% yield) as a white powder.

[1861] ¹ H NMR (DMSO-de) δ ppm:

[1862] 1.12 (3H, s), 3.24 (3H, s), 4.09 (2H, s), 4.13 (2H, s), 5.62 (1H, br), 8, 34 (1H,

s).

Example 18

Preparation of (S) -2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole [1863] (S) -2-chloro-1- (2-hydroxy-2-methyl-3-methanesulfonyloxypropyl ) -4-nitroimidazole prepared in Example 17 (3.02 g, 9.51 mmol) was dissolved in methylene chloride (30 ml). DBU (1.7 ml, 11.41 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with 3 N hydrochloric acid (30 ml) and saturated saline solution (20 ml) in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving (S) -2-chloro-1- (2-methyloxyran-2- ilmethyl) -4nitroimidazole (1.89 g, 91% yield) as a light yellow solid.

[1864] 93.2% optical purity e.e.

[1865] [a] d ²⁷ = -29.15 ^o (concentration: 1.18, CHCb) [1866] ¹ H NMR (CDCb) δ ppm:

[1867] 1.39 (3H, s), 2.63 (1H, d, J = 4.0 Hz), 2.79 (1H, d, J = 4.0 Hz), 4.00 (1H, d,

J = 14.9 Hz), 4.38 (1H, d, J = 14.9 Hz), 7.88 (1H, s).

Example 19

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526/854

Preparation of 2-ter-butoxymethyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1868] 2,4-Dinitro-1 H-imidazole (10 g, 63.3 mmol), 2- ter-butoxymethyloxirane (27 ml,

189 mmol) and sodium acetate (5.19 g, 189 mmol) were suspended in ethanol (100 ml) followed by stirring at reflux for 17 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving 2-ter-butoxymethyl-6-nitro-2,3 dihydroimidazo [2,1-b] oxazole (3, 2 g, 21% yield) as a white powder.

[1869] ¹ H NMR (CDCb) δ ppm:

[1870] 1.18 (9H, s), 3.63 - 3.80 (2H, m), 4.22 - 4.36 (2H, m), 5.27 - 5.42 (1H, m) ,

7.53 (1H, s).

[1871] Using 2-methyl-2- (2-methoxymethoxyethyl) oxirane, 2-ethyl-2-methoxymethoxymethyloxirane or 2-isopropyl-2-methoxymethoxymethyloxirane, compounds of Examples 20 to 22 were obtained in the same manner as in Example 19.

Example 20 2- (2-Methoxyethoxyethyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1872] White powder, 48% yield, MS = 257

Example 21

2-Ethyl-2-methoxymethoxymethyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1873] Light yellow powder, 49% yield [1874] ¹ H NMR (DMSO-d ₆ ) δ ppm :

[1875] 0.91 (3H, t, J = 7.5 Hz), 1.91 (2H, q, J = 7.5 Hz), 3.24 (3H, s), 3.72 (1H, d,

J = 11.2 Hz), 3.78 (1H, d, J = 11.2 Hz), 4.15 (1H, d, J = 11.2 Hz), 4.23 (1H, d, J = 11.2 Hz), 4.59 (2H, s), 8.10 (1H, s).

Example 22 2-lsopropyl-2-methoxymethoxymethyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1876] Light yellow powder, 90% yield [1877] ¹ H NMR (DMSO-d ₆ ) δ ppm:

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527/854 [1878] 0.94 (6H, d, J = 6.9 Hz), 2.16-2.32 (1H, m), 3.24 (3H, s), 3.76 (1H, d, J =

13.0 Hz), 3.82 (1H, d, J = 13.0 Hz), 4.18 (1H, d, J = 13.0 Hz), 4.25 (1H, d, J = 13, 0 Hz),

4.59 (2H, s), 8.09 (1H, s).

Example 23

Preparation of 2-chloro-1 - (2-hydroxy-4-methoxymethoxybutyl) -4-nitroimidazole [1879] Sodium acetate (3.51 g, 42.82 mmol) and 2- (2-methoxyethoxyethyl) oxirane were added (10.3 g, 77.86 mmol) to 2-chloro-4-nitro-1 H-imidazole (5.74 g, 38.93 mmol) in ethanol (60 ml), and the resulting mixture was stirred at reflux for 13.5 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and then crystallized from methylene chloride -disopropyl ether giving 2-chloro-1- (2-hydroxy-4-methoxymethoxybutyl) -4-nitroimidazole (8.51 g, 78% yield) as a light yellow powder.

[1880] ¹ H NMR (CDCb) δ ppm:

[1881] 1.67 (2H, m), 3.38 (3H, s), 3.46 (1H, d, J = 2.4 Hz), 3.78 - 3.83 (2H, m), 4.00 (1H, dd, J = 7.6 Hz, 14.3 Hz), 4.11 - 4.21 (2H, m), 4.63 (2H, s), 7.96 (1H, s ).

[1882] Using 2-methyl-2-methoxymethoxymethyloxirane a compound of Example 24 was obtained in the same manner as in Example 23.

Example 24

2-chloro-1- (2-hydroxy-3-methoxymethoxypropyl) -4-nitroimidazole [1883] Colorless liquid, 63% yield [1884] ¹ H NMR (CDCb) δ ppm:

[1885] 1.20 (3H, s), 3.08 (1H, s), 3.42 (3H, s), 3.53 (2H, dd, J = 10.4 Hz, 13.8 Hz) ,

4.67 (2H, s), 8.01 (1H, s).

Example 25

Preparation of 2- (2-methoxyethoxyethyl) -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1886] Sodium hydride (1.33 g, 33.23 mmol) was added to a solution 2-chloro-1- (2-hydroxy-4-methoxymethoxybutyl) -4-nitroimidazole prepared in Example 23 (8.45

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528/854 g, 30.21 mmol) in 1,4-dioxane (100 ml) with cooling in an ice bath followed by stirring at reflux for 40 hours. The reaction mixture was concentrated under reduced pressure, and cooled in an ice bath. Water was added to the residue, and the resulting mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from methylene chloride-diisopropyl ether giving 2- (2-methoxymethoxyethyl) -6-nitro-2, 3-dihydroimidazo [2,1-b] oxazole (3.4 g, 47% yield) as a light yellow powder.

[1887] ¹ H NMR (CDCb) δ ppm:

[1888] 2.11 - 2.35 (2H, m), 3.36 (3H, s), 3.75 (2H, dd, J = 4.8 Hz, 6.8 Hz), 4.08 ( 1H, dd, J = 7.6 Hz, 10.3 Hz), 4.40 (1H, dd, J = 7.6 Hz, 10.3 Hz), 4.61 (2H, s), 5.43 - 5.54 (1H, m), 7.53 (1H, s).

[1889] Using 2-chloro-1- (2-hydroxy-3-methoxymethoxypropyl) -4-nitroimidazole prepared in Example 24, a compound of Example 26 was obtained in the same manner as in Example 25.

Example 26 2-Methoxymethoxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1890] Light yellow powder, 38% yield [1891] ¹ H NMR (CDCb) δ ppm:

[1892] 1.66 (3H, s), 3.34 (3H, s), 3.63 (1H, d, J = 11.0 Hz), 3.84 (1H, d, J = 11.0

Hz), 3.93 (1H, d, J = 9.9 Hz), 4.37 (1H, d, J = 9.9 Hz), 4.62 (2H, s), 7.52 (1H, s). Example 27

Preparation of (R) -2-chloro-1 - (2-hydroxy-3-methoxymethoxy-2-methylpropyl) -4-nitroimidazole [1893] (R) -2-chloro-1- (2,3-dihydroxy-2 -methylpropyl) -4-nitroimidazole prepared in Example 10 (7.4 g, 31 mmol) was dissolved in methylene chloride (120 ml). N, N-diisopropylethylamine (13.1 ml, 74 mmol) and chloromethylmethyl ether (7.1 ml, 74 mmol) were added to the solution followed by stirring at room temperature for 46 hours. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by means of chromatography

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529/854 column on silica gel (methylene chloride / ethyl acetate = 9/1) giving (R) -2-chloro-

1- (2-hydroxy-3-methoxymethoxy-2-methylpropyl) -4-nitroimidazole (6.0 g, 69% yield) as a light yellow oil.

[1894] ¹ H NMR (CDCb) δ ppm:

[1895] 1.20 (3H, s), 3.08 (1H, s), 3.42 (3H, s), 3.50 (1H, d, J = 10.4 Hz), 3.55 ( 1H, d, J = 10.4 Hz), 4.05 (1H, d, J = 14.4 Hz), 4.15 (1H, d, J = 14.4 Hz), 4.67 (2H, s), 8.01 (1H, s).

Example 28

Preparation of (R) -2-methoxymethoxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1896] Sodium hydride (1.0 g, 25 mmol) was added to a solution of (R) -2chloro-1 - (2-hydroxy-3-methoxymethoxy-2-methylpropyl) -4-nitroimidazole prepared in Example 27 (6.0 g, 21 mmol) in DMF (30 ml) with cooling in ice bath followed by stirring at room temperature for 1.5 hours. Ice water was added to the reaction mixture, and the precipitates were removed by filtration and washed with water giving (R) -2-methoxymethoxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole (3.1 g, 59% yield) as a yellow solid.

[1897] ¹ H NMR (CDCb) δ ppm:

[1898] 1.66 (3H, s), 3.34 (3H, s), 3.63 (1H, d, J = 11.0 Hz), 3.84 (1H, d, J = 11.0

Hz), 3.93 (1H, d, J = 10.0 Hz), 4.42 (1H, d, J = 10.0 Hz), 4.63 (2H, s), 7.52 (1H, s). Example 29

Preparation of 2-chloro-1 - (5-acetoxy-2-hydroxy-2-methylpentyl) -4-nitroimidazole [1899] 2-chloro-4-nitro-1 H-imidazole (6.8 g, 43 mmol), 2- (3-acetoxypropyl) -2methyloxirane (5.8 g, 39.3 mmol) and sodium acetate (3.9 g, 47.6 mmol) were suspended in ethanol (60 ml) followed by stirring at reflux for one overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride twice. The organic phases were combined, washing with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution in that order, drying over sodium sulfate and then filtering. The filtrate was concentrated under reduced pressure giving 2-chloro-1- (5-acetoxy-2-hydroxy-2-methylpentyl)

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530/854

4-nitroimidazole (9.5 g, 79% yield) as a light brown oil.

[1900] ¹ H NMR (CDCb) δ ppm:

[1901] 1.21 (3H, s), 1.50 -1.81 (4H, m), 2.05 (3H, s), 3.91 - 4.12 (4H, m), 8.02 (1H,

s).

Example 30

Preparation of 2- (3-acetoxypropyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1902] Using 2-chloro-1- (5-acetoxy-2-hydroxy) 2-methylpentyl) -4-nitroimidazole (9.5 g, 31.1 mmol) prepared in Example 29, 2- (3-acetoxypropyl) -2-methyl-6-nitro2,3-dihydroimidazo [2,1- b] oxazole (5.2 g, 62% yield) as a light orange powder in the same manner as in Example 25.

[1903] ¹ H NMR (CDCb) δ ppm:

[1904] 1.67 (3H, s), 1.67 - 2.00 (4H, m), 2.05 (3H, s), 3.91 -4.14 (4H, m), 7.52 (1H,

s).

Example 31

Preparation of 2- (2-hydroxyethyl) -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1905] Trifluoroacetic acid (2 ml) was added to a solution of 2- (2 methoxyethoxyethyl) -6 -nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 25 (0.2 g, 0.822 mmol) in methylene chloride (10 ml) followed by stirring at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1), and crystallized from methanol-diisopropyl ether giving 2- (2hydroxyethyl) - 6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (0.11 g, 65% yield) as a light yellow powder.

[1906] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1907] 1.92 - 2.14 (2H, m), 3.52 - 3.63 (2H, m), 4.05 (1H, dd, J = 7.6 Hz, 10.6 Hz),

4.43 (1H, dd, J = 7.6 Hz, 10.6 Hz), 4.72 (1H, t, J = 2.7 Hz), 5.38 - 5.53 (1H, m), 8.12 (1H, s).

Example 32

Preparation of 2-hydroxymethyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1908] Using 2-ter-butoxymethyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole

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531/854 prepared in Example 19 (5.82 g, 24.1 mmol) 2-hydroxymethyl-6-nitro-2,3 dihydroimidazo [2,1-b] oxazole (4.25 g, 95% yield) was obtained ) as a white powder in the same way as in Example 31.

[1909] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1910] 3.55 - 3.67 (1H, m), 3.72 - 3.88 (1H, m), 4.12 (1H, dd, J = 6.5 Hz, 10.5 Hz),

4.36 (1H, t, J = 10.4 Hz), 5.25 - 5.50 (2H, m), 8.11 (1H, s).

Example 33

Preparation of 2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1911] Using 2-methoxymethoxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2 , 1b] oxazole prepared in Example 26 (4.14 g, 38 mmol) 2-hydroxymethyl-2-methyl6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (2.17 g, yield 64%) as a light yellow powder in the same manner as in Example 31.

[1912] Melting point 166-168 ° C [1913] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1914] 1.51 (3H, s), 3.53 (1H, d, J = 12.1 Hz), 3.64 (1H, d, J = 12.1 Hz), 4.03 (1H, d, J = 10.6 Hz), 4.24 (1H, d, J = 10.6 Hz), 5.40 (1H, br), 8.10 (1H, s).

Example 34

Preparation of 2- (2-hydroxyethyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1915] Using 2- (2-methoxymethoxyethyl) -2-methyl-6-nitro -2,3-dihydroimidazo [2,1b] oxazole prepared in Example 20 (13.4 g, 52.1 mmol) 2- (2-hydroxyethyl) -2methyl-6-nitro-2,3-dihydroimidazo [ 2,1-b] oxazole (2.32 g, 21% yield) as a light yellow powder in the same manner as in Example 31.

[1916] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1917] 1.58 (3H, s), 1.93 - 2.17 (2H, m), 3.59 (2H, t, J = 6.4 Hz), 4.04 (1H, d J =

10.9 Hz), 4.33 (d, 1H, J = 10.9 Hz), 8.11 (1H, s).

Example 35

Preparation of 2-ethyl-2-hydroxymethyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol [1918] 2-Ethyl-2-methoxymethoxymethyl-6-nitro-2,3-dihydroimidazo [2, 1-b] oxazole prepared in Example 21 (21.5 g, 83.7 mmol) was suspended in methanol (430 ml). Concentrated hydrochloric acid (2.15 ml) was added to this suspension, followed by

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532/854 stirring at reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the precipitates were removed by filtration giving 2-ethyl-2-hydroxymethyl6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (7.14 g, yield 40 %) as a light yellow powder.

[1919] ¹ H NMR (DMSO-de) δ ppm:

[1920] 0.89 (3H, t, J = 7.4 Hz), 1.95 (2H, q, J = 7.4 Hz), 3.53 - 3.69 (2H, m), 4, 08 (1H, d, J = 10.8 Hz), 4.21 (1H, d, J = 10.8 Hz), 5.39 (t, 1H, J = 5.6 Hz), 8.09 ( 1H, s).

[1921] Using corresponding starting materials, a compound of Example 36 was obtained in the same way as in Example 35.

Example 36

2-hydroxymethyl-2-isopropyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1922] Light yellow powder, 50% yield [1923] ¹ H NMR (DMSO-d ₆ ) δ ppm :

[1924] 0.91 (6H, d, J = 6.9 Hz), 2.12 - 2.23 (1H, m), 3.60 - 3.77 (2H, m), 4.16 (2H ,

s), 5.35 (1H, t, J = 5.6 Hz), 8.08 (1H, s).

Example 37

Preparation of (R) -2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1925] Thfluoroacetic acid (15 ml) was added to a solution of (R) -2methoxymethoxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 28 (3.1 g, 13 mmol) in methylene chloride (30 ml) followed by stirring at temperature room for 25 hours. The reaction mixture was concentrated under reduced pressure. Methanol was added to the solution, and the resulting mixture was concentrated under reduced pressure. 2-Propanol was added to the residue and the precipitates were removed by filtration and washed with 2-propanol giving (R) -2hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole ( 1.2 g, 46% yield) as a light yellow powder.

[1926] Melting point 162-163 ° C [1927] Optical purity 97% e.e.

[1928] [oc] d ²⁶ = -19.01 ° (concentration: 0.526, DMSO)

Example 38

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533/854

Preparation of 2-methyl-2- (3-hydroxypropyl) -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [1929] A mixture of 2- (3-acetoxypropyl) -2-methyl-6 -nitro-2,3-dihydroimidazo [2,1b] oxazole prepared in Example 30 (3.2 g, 11.88 mmol), potassium carbonate (320 mg, 2.32 mmol) and methanol (35 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 25/1) giving 2-methyl-2- (3-hydroxypropyl) -6 -nitro-2,3-dihydroimidazo [2,1-b] oxazole (2.1 g, 78%) as a light yellow powder.

[1930] ¹ H NMR (CDCb) δ ppm:

[1931] 1.67 - 1.72 (5H, m), 1.91 - 2.07 (2H, m), 3.51 - 3.65 (2H, m), 4.01 (1H, d, J = 10.5 Hz), 4.15 (1H, d, J = 10.5 Hz), 7.66 (1H, s).

Example 39

Preparation of 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl methanesulfonate [1932] Methanesulfonyl chloride (1.4 ml, 18.09 mmol) in methylene chloride (10 ml) was added dropwise to a mixture of 2-methyl-2- (3-hydroxypropyl) -6nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 38 (2, 1 g, 9.24 mmol), triethylamine (2.8 g, 20.09 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol) and methylene chloride (80 ml) with cooling in an ice bath followed by stirring at room temperature overnight. The reaction mixture was concentrated. 10% hydrochloric acid was added to the residue, and the resulting mixture was stirred for 30 minutes with cooling in an ice bath. The precipitates were removed by filtration and washed with water giving 3- (2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl methanesulfonate (2.6 g, yield 92 %) as a white powder.

[1933] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1934] 1.58 (3H, s), 1.65 - 2.02 (4H, m), 3.17 (3H, s), 4.05 - 4.26 (4H, m), 8.12 (1H,

s).

[1935] Using corresponding starting materials, compounds of Examples 40 to 42 were obtained in the same manner as in Example 39.

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534/854

Example 40

6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl methanesulfonate [1936] Light yellow powder, 82% yield [1937] ¹ H NMR (DMSO-de) δ ppm:

[1938] 3.25 (3H, s), 4.11 (1H, dd, J = 6.6 Hz, 11.0 Hz), 4.47 (1H, t, J = 9.1 Hz),

4.55 - 4.70 (2H, m), 5.60 - 5.75 (1H, m), 8.14 (1H, s).

Example 41

2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl methanesulfonate [1939] Light yellow powder, 87% yield [1940] ¹ H NMR (DMSO-de) δ ppm:

[1941] 1.64 (3H, s), 3.24 (3H, s), 4.17 (1H, d, J = 11.2 Hz), 4.27 (1H, d, J = 11.2

Hz), 4.52 (2H, br), 8.14 (1H, s).

Example 42

2- (2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl methanesulfonate [1942] Light yellow powder, 87% yield [1943] ¹ H NMR ( DMSO-de) δ ppm:

[1944] 1.61 (3H, s), 2.38 (2H, t, J = 6.5 Hz), 3.19 (3H, s), 4.11 (1H, d, J = 11.0 Hz),

4.25 (1H, d, J = 11.0 Hz), 4.36 (2H, t, J = 6.5 Hz), 8.14 (1H, s).

Example 43

Preparation of tert-butyl 5- (2-chloro-4-nitroimidazol-1-yl) -4-hydroxy-4-methylpentanoate [1945] Sodium acetate (0.59 g, 7.18 mmol) was added to a suspension of tert-butyl 3 (2-methyloxyran-2-yl) propionate (1.00 g, 5.39 mmol) and 2-chloro-4-nitro-1 Himidazole (0.53 g, 3.59 mmol ) in ethanol (5 ml) followed by stirring at reflux for 6 hours. Insoluble materials were removed by means of filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 5- (2-chloro-4nitroimidazol-1-yl) -4-hydroxy-4-methylpentanoate butyl (0.94 g, 78% yield) as a light yellow oil.

[1946] ¹ H NMR (CDCb) δ ppm:

[1947] 1.17 (3H, s), 1.45 (9H, s), 1.78 -1.87 (2H, m), 2.43 - 2.54 (2H, m), 3.59 (1H,

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535/854 br), 3.99 (2H, s), 8.06 (1H, s).

Example 44

Preparation of terbutyl 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propionate [1948] Sodium hydride (0.12 g, 3 , 07 mmol) to a solution of ter-butyl 5- (2chloro-4-nitroimidazol-1-yl) -4-hydroxy-4-methylpentanoate prepared in Example 43 (0.93 g, 2.79 mmol) in 1 , 4-dioxane (10 ml) with cooling in an ice bath followed by stirring at reflux for 7.5 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the solution, and the resulting mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was treated with diethyl ether giving tert-butyl 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propionate (0.35 g, 42 %) as a white solid.

[1949] ¹ H NMR (CDCb) δ ppm:

[1950] 1.45 (9H, s), 1.65 (3H, s), 2.12 - 2.25 (2H, m), 2.37 - 2.46 (2H, m), 3.98 (1H, d, J = 10.3 Hz), 4.10 (1H, d, J = 10.3 Hz), 7.52 (1H, s).

Example 45

Preparation of 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propionic acid [1951] Trifluoroacetic acid (2 ml) was added to a solution of 3 - tert-butyl propionate (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) prepared in Example 44 (0.72 g, 2.42 mmol) in methylene chloride (14 ml) followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from ethanol-methylene chloride giving acid

3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propionic (0.30 g, 51%) as a light yellow solid.

[1952] ¹ H NMR (DMSO-de) δ ppm:

[1953] 1.32 (3H, s), 1.91 -2.09 (1H, m), 2.12-2.26 (1H, m), 2.41 -2.74 (2H, m) ,

3.89 (2H, s), 7.96 (1H, s), 12.19 (1H, br).

Example 46

Preparation of 2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) benzoxazole

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536/854 [1954] Sodium hydride (77 mg, 1.9 mmol) was added to a solution of 2hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 33 (0.32 g, 1.6 mmol) in DMF (3 ml) with cooling in an ice bath followed by stirring at 0 ° C for 30 minutes. 2 Chlorobenzoxazole (0.30 g, 1.9 mmol) in DMF (3 ml) was added to the reaction mixture with cooling in an ice bath followed by stirring at room temperature for 44 hours. Ice water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and recrystallized from acetonitrile-isopropanol giving 2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethoxy) benzoxazole (0.20 g, 39%) as a light yellow solid.

[1955] Melting point 200-203 ° C

Example 47

Preparation of (R) -2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i i m ethoxy) benzoxazo I [1956] Sodium hydride (0, 1 g, 2.4 mmol) to a solution of (R) -2hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 37 (0.40 g, 2 , 0 mmol) in DMF (4 ml) followed by stirring for 30 minutes with cooling in an ice bath. 2-Chlorobenzoxazole (0.38 g, 2.4 mmol) in DMF (4 ml) was added to the reaction mixture with cooling in an ice bath followed by stirring at room temperature for 48 hours. Ice water was added to the reaction mixture. The precipitates were removed by filtration, washed with water, and then recrystallized from acetonitrile-isopropanol giving (R) -2- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) benzoxazole (0.15 g, 24% yield) as a light yellow solid.

[1957] Melting point 232-233 ° C [1958] Optical purity> 99.5% e.e.

[1959] [oc] d ²⁶ = + 11.20 ° (concentration: 0.518, DMSO)

Example 48

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537/854

Preparation of 2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethylthio) benzoxazole [1960] Sodium hydride (50 mg, 1.25 mmol) was added to an mixture of 2mercaptobenzoxazole (200 mg, 1.3 mmol) and DMF (3 ml) followed by stirring at room temperature for 1 hour. 2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl methanesulfonate prepared in Example 41 (330 mg, 1.2 mmol) was added to the reaction mixture, and The resulting mixture was stirred at 6070 ° C for 5 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washing with 5% sodium hydroxide solution and water three times, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving 2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b ] oxazol-2-ylmethylthio) benzoxazole (37 mg, 9% yield) as a white powder.

[1961] Melting point 163-166 ° C

Example 49

Preparation of 2- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2yl) ethylthio] benzoxazole [1962] Using 2- (2-methyl-6- methanesulfonate nitro-2,3-dihydroimidazo [2,1b] oxazol-2-yl) ethyl prepared in Example 42 (300 mg, 1 mmol) 2- [2- (2-methyl6-nitro-2,3-dihydroimidazo) was obtained [2,1-b] oxazol-2-yl) ethylthio] benzoxazole (296 mg, 83% yield) as a white powder in the same manner as in Example 48.

[1963] Melting point 174-175 ° C

Example 50

Preparation of 1 - (2-chloro-4-nitroimidazole-1-yl) -2-methyl-3- (1-phenyl-1 H-tetrazol-5-thio) propane-2-ol [1964] A mixture of 2-chlorine -4-nitro-1 H-imidazole (1.2 g, 8.13 mmol), 5- (2-methyloxyran-2-ylmethylthio) -1 -phenyl-1 H-tetrazole (1.9 g, 7.65 mmol) , sodium acetate (700 mg, 8.53 mmol) and ethanol (20 ml) was stirred at reflux overnight. THE

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538/854 reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washing with a saturated aqueous solution of sodium bicarbonate twice, then washing with water and a saturated saline solution, in that order, drying over sodium sulfate and then filtering. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving 1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3 (1- phenyl-1 H-tetrazol-5-ylthio) propane-2-ol giving (2.1 g, 69% yield) as a light yellow powder.

[1965] ¹ H NMR (CDCb) δ ppm:

[1966] 1.38 (3H, s), 3.54 (1H, d, J = 14.8 Hz), 3.62 (1H, d, J = 14.8 Hz), 4.19 (2H,

s), 4.58 (1H, s), 7.50 - 7.67 (5H, m), 8.08 (1H, s).

Example 51

Preparation of 2-methyl-6-nitro-2- (1-phenyl-1 H-tetrazol-5-ylthiomethyl) -2,3-dihydroimidazo [2,1b] oxazol [1967] Sodium hydride (220 mg , 5.5 mmol) to a mixture of 1- (2chloro-4-nitroimidazol-1-yl) -2-methyl 1-3- (1-phenyl-1 H-tetrazol-5-yl) propane-2-ol prepared in Example 50 (2.1 g, 5.3 mmol) and 1,4-dioxane (40 ml), and the resulting mixture was stirred at reflux for 24 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washing with water and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving 2-methyl-6-nitro-2- (1-phenyl-1 H-tetrazol-5-ylthiomethyl) -2,3-dihydroimidazo [2,1-b] oxazole (500 mg, 26% yield) as a light brown powder.

[1968] Fusion bridge 140-147 ° C

Example 52

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539/854

Preparation of tert-butyl (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxycarbonylamino) [1969] Glycine tert-butyl ester monohydrochloride (0.52 g, 2.27 mmol) in methylene chloride (5 ml) and N, N-diisopropylethylamine (1.05 ml, 4.53 mmol) were added to a triphosgene (0.30 g, 0.76 mmol) in methylene chloride (10 ml) with cooling in an ice bath followed by stirring at room temperature for 2 hours. Insoluble materials were removed by means of filtration, and the filtrate was concentrated under reduced pressure. The residue was added to a solution of 2-hydroxymethyl-2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 33 (0.30 g, 1.51 mmol) in DMF (3 ml) with cooling in an ice bath. Then cuprous chloride (75 mg, 0.76 mmol) was added to the resulting mixture, followed by stirring at room temperature for 22 hours. Water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (nhexane / ethyl acetate = 3/2) giving (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole-2ylmethoxycarbonylamino ) tert-butyl acetate (40 mg, 7% yield) as a white solid.

[1970] Melting point 104-106 ° C

Example 53

Preparation of 6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl (4morpholinophenyl) carbamate [1971] 1,1'-carbonyldiimidazole (0.44 g, 2.69 mmol) was added to a solution of

4-morpholinoniline (0.40 g, 2.24 mmol) in THF (4 ml) followed by stirring for 2 hours with cooling in an ice bath. The reaction mixture was filtered and washed with diethyl ether. The filtrate was added to a solution of 2-hydroxymethyl-6-nitro2,3-dihydroimidazo [2,1-b] oxazole (0.30 g, 1.62 mmol) in DMF (3 ml) with cooling in an ice bath . Then cuprous chloride (75 mg, 0.76 mmol) was added to the resulting mixture, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, the resulting mixture was extracted with acetate

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540/854 of ethyl, and the extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / acetone = 9/1), and washed with methylene chloride-ethyl acetate giving 6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl (4morpholinophenyl) carbamate (34 mg, 5% yield) as a white solid.

[1972] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1973] 2.93 - 3.09 (4H, m), 3.64 - 3.80 (4H, m), 4.13 (1H, dd, J = 6.8 Hz, 10.9 Hz),

4.34-4.55 (3H, m), 5.55 - 5.73 (1H, m), 6.77-6.95 (2H, m), 7.18-7.41 (2H, m ), 8.15 (1H, s), 9.52 (1H, br).

Example 54

Preparation of 2- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl 4chlorophenylcarbamate [1974] 4-Chlorophenylisocyanate (169 ml, 1.1 mmol) and cuprous chloride were added (50 mg, 0.5 mmol) to a solution of 2-hydroxyethyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole prepared in Example 31 (0.2 g, 1.0 mmol) in DMF ( 5 ml) with cooling in an ice bath, followed by stirring at room temperature for 4 hours. The mixture was cooled in an ice bath and received the addition of 10% hydrochloric acid. The resulting mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from methylene chloride-isopropyl ether giving 2- (6-nitro-2,3-4-chlorophenylcarbamate) -dihydroimidazo [2,1-b] oxazol-2-yl) ethyl (0.16 g, 45% yield) as a white solid.

[1975] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[1976] 2.16 - 2.38 (2H, m), 4.08 (1H, dd, J = 7.4 Hz, 10.6 Hz), 4.16 - 4.36 (2H, m),

4.47 (1H, dd, J = 7.4 Hz, 10, 6 Hz), 5.44 - 5.55 (1H, m), 7.30 - 7.36 (2H, m), 7.46 - 7.52 (2H, m), 8.14 (1H, s), 9.83 (1H, br).

[1977] Using phenylisocyanate and 2-hydroxyethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole, 2-ethyl-2-hydroxymethyl-6-nitro-2,3-dihydroimidazo [2, 1-b] oxazole or 2-hydroxymethyl-2-isopropyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole was obtained

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541/854 compounds of Examples 55 to 57 in the same manner as in Example 54. Additionally, using 2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole and 3-fluorophenylisocyanate or 4-ter-butoxycarbonylphenylisocyanate compounds of Examples 58 and 59 were obtained in the same manner as in Example 54.

Example 55

2- (2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl phenylcarbamate [1978] Yellow solid, 17% yield [1979] ¹ H NMR (DMSO- of) δ ppm:

[1980] 1.63 (3H, s), 2.30 (2H, t, J = 6.9 Hz), 4.13 (1H, d, J = 10.9 Hz), 4.21 -4, 32 (3H, m), 6.96 - 7.02 (1H, m), 7.24 - 7.27 (2H, m), 7.43 - 7.46 (2H, m), 8.12 ( 1H, s), 9.60 (1H, br).

Example 56 2-Ethyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl phenylcarbamate [1981] White solid, 60% yield [1982] ¹ H NMR (DMSO-de) δ ppm:

[1983] 0.93 (3H, t, J = 7.4 Hz), 1.89-2.11 (2H, m), 4.19 - 4.29 (2H, m), 4.39-4 , 50 (2H, m), 6.99 (1H, t, J = 7.2 Hz), 7.23 - 7.29 (2H, m), 7.34 - 7.55 (2H, m), 8.14 (1H, s), 9.70 (1H, br).

Example 57 2-Isopropyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl phenylcarbamate [1984] White solid, 73% yield [1985] ¹ H NMR (DMSO-de) δ ppm:

[1986] 0.97 (6H, dd, J = 2.7 Hz, 6.9 Hz), 2.25 - 2.39 (1H, m), 4.20 (1H, d, J = 11.4

Hz), 4.30 (1H, d, J = 11.4 Hz), 4.48 (2H, s), 6.99 (1H, t, J = 7.1 Hz), 7.23 - 7, 29 (2H, m), 7.32-7.52 (2H, m), 8.13 (1H, s), 9.67 (1H, br).

Example 58

3-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl fluorophenylcarbamate [1987] White solid, 71% yield [1988] Melting point 168-169 ° C

Example 59

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4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxycarbonylamino) ter-butyl benzoate [1989] White solid, 32% yield [1990] Melting point 177-178 ° C

Example 60

Preparation of 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxycarbonylamino) benzoic acid [1991] Trifluoroacetic acid (1 ml) was added to a suspension of 4- ( Ter-butyl 2-methyl6-nitro-2,2-dihydroimidazo [2,1-b] oxazol-2-ylmethoxycarbonylamino) benzoate prepared in Example 59 (185 ml, 0.44 mmol) in methylene chloride (10 ml) with cooling in an ice bath, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was washed with ethyl acetate giving 4- (2-methyl-6-nitro-2,3-diidromidazo [2,1-b] oxazol-2ylmethoxycarbonylamino) benzoic acid (50 mg, 31% yield) as a solid White. [1992] Melting point 248 ° C (decomposition)

Example 61

Preparation of 2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl 4-chlorophenylcarbamate [1993] 4-2-methyloxyran-2-ylmethyl 4-chlorophenylcarbamate (1.1 g, 4 , 4 mmol) and 2,4-dinitro-1 H-imidazole (0.35 g, 2.2 mmol) were suspended in ethanol (1 ml), and the resulting mixture was stirred at room temperature for 24 hours. Then, sodium acetate (0.36 g, 4.4 mmol) and ethanol (2 ml) were added to the mixture, followed by stirring at reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was added with water, and the resulting mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was crystallized from methylene chloride-diethyl ether giving 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl 4-chlorophenylcarbamate (0.17 g, 22% yield ) as a light yellow solid.

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543/854 [1994] Melting point 179-181 ° C

Example 62

Preparation of 3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl N- (4-chlorophenyl) N-methylcarbamate [1995] N- (4-chlorophenyl) -N-methylcarbamate 2-methyloxyran-2-ylmethyl (1.7 g, 6.6 mmol) and 2-chloro-4-nitro-1 H-imodazole (0.98 g, 6.6 mmol) were suspended in ethanol (10 ml) [e] sodium acetate (0.85 g, 10 mmol) was added, followed by stirring at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the resulting mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 3- (2-chlorophenyl-N-methylcarbamate) 3-- (2-chloro-4-nitroimidazole- 1-yl) -2hydroxy-2-methylpropyl (2.7 g, quantitative) as a light yellow oil.

[1996] ¹ H NMR (CDCb) δ ppm:

[1997] 1.15 (3H, br), 3.28 (3H, s), 3.78 - 4.28 (4H, m), 7.11 - 7.24 (2H, m), 7.30 7.41 (2H, m), 7.90 (1H, br).

Example 63

Preparation of 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl N- (4-chlorophenyl) -N-methylcarbamate [1998] Sodium hydride (0.32) g, 7.9 mmol) to a solution of 3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl N- (4-chlorophenyl) -N-methylcarbamate prepared in Example 62 (2 , 7 g, 6.6 mmol) in 1,4-dioxane (30 ml) with cooling in an ice bath, followed by stirring at reflux for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was cooled in an ice bath and water was added, and the resulting solution was extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) and crystallized from methylene chloride-ethanol giving N- (4-chlorophenyl) -N-methylcarbamate of 2-methyl-6-nitro-2,3- dihydroimidazo [2,1-b] oxazol-2-ylmethyl (0.88 g,

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544/854 yield 36%) as a white solid.

[1999] Melting point 146-148 ° C

Example 64

Preparation of (R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-4-chlorophenylcarbamate

2-methylpropyl [2000] A solution, in THF (15 ml), of 4-chlorophenylisocyanate (1.3 g, 85 mmol) and triethylamine (0.1 ml) was added to a suspension of (R) -2- chloro-1- (2,3-dihydroxy-2methylpropyl) -4-nitroimidazole prepared in Example 10 (1.5 g, 6.5 mmol) in THF (30 ml), followed by stirring at room temperature for 19 hours. Insoluble materials were removed by means of filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving (R) -3- (2-chloro-4-nitroimidazole-1-yl) 4-chlorophenylcarbamate ) -2-hydroxy-2-methylpropyl (2.1 g, 83% yield) as a white solid.

[2001] ¹ H NMR (DMSO-de) δ ppm:

[2002] 1.15 (3H, s), 3.99 (2H, s), 4.07 (2H, s), 7.29 - 7.39 (2H, m), 7.45 - 7.58 (2H,

m), 8.33 (1H, s), 9.86 (1H, br).

[2003] Using various types of corresponding phenylisocyanates, compounds of Examples 65 to 69 were obtained in the same manner as in Example 64. Additionally, using benzylisocyanate or methylisocyanate, compounds of Examples 70 and 71 were obtained in the same manner as in Example 64.

Example 65

3- (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl chlorophenylcarbamate [2004] 41% yield [2005] ¹ H NMR (DMSO-de) δ ppm:

[2006] 1.15 (3H, s), 4.00 (2H, s), 4.13 (2H, s), 5.41 (1H, s), 7.04 - 7.09 (1H, m ),

7.29 - 7.41 (2H, m), 7.55 - 7.66 (1H, m), 8.33 (1H, s), 9.93 (1H, br).

Example 66

4- (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl bromophenylcarbamate [2007] 62% yield

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545/854 [2008] ¹ H NMR (DMSO-de) δ ppm:

[2009] 1.15 (3H, s), 3.99 (2H, s), 4.13 (2H, s), 5.40 (1H, s), 7.34 - 7.53 (4H, m ),

8.33 (1H, s), 9.86 (1H, br).

Example 67

(R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-h idroxy-2-methylpropyl 4-trifluoromethylphenylcarbamate [2010] 83% yield [2011] ¹ H NMR (DMSO-de) δ ppm :

[2012] 1.16 (3H, s), 4.02 (2H, s), 4.14 (2H, s), 5.42 (1H, s), 7.58 - 7.74 (4H, m ),

8.34 (1H, s), 10.14 (1H, br).

Example 68

(R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-h idroxy-2methylpropyl 4-trifluoromethoxyphenylcarbamate [2013] 58% yield [2014] ¹ H NMR (DMSO-de) δ ppm :

[2015] 1.15 (3H, s), 3.99 (2H, s), 4.13 (2H, s), 5.41 (1H, s), 7.31 (2H, d, J = 8 , 5 Hz),

7.58 (2H, d, J = 8.5 Hz), 8.33 (1H, s), 9.92 (1H, br).

Example 69

(R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl 4-fluorophenylcarbamate [2016] 95% yield [2017] ¹ H NMR (DMSO-de) δ ppm:

[2018] 1.15 (3H, s), 3.98 (2H, s), 4.12 (2H, s), 5.39 (1H, s), 7.10 - 7.17 (2H, m ),

7.45 - 7.51 (2H, m), 8.33 (1H, s), 9.73 (1H, br).

Example 70 (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl benzylcarbamate [2019] 72% yield [2020] ¹ H NMR (CDCb) δ ppm:

[2021] 1.20 (3H, s), 3.61 (1H, br), 3.97 - 4.04 (3H, m), 4.23 (1H, d, J = 12.0 Hz),

4.70-4.89 (1H, m), 7.13-7.39 (5H, m), 8.01 (1H, s).

Example 71

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(R) -3- (2-Chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl methylcarbamate [2022] 73% yield [2023] ¹ H NMR (CDCb) δ ppm:

[2024] 1.21 (3H, s), 2.80 (3H, d, J = 4.8 Hz), 3.57 (1H, br), 3.98 - 4.16 (3H, m), 4.24 (1H, d, J = 12.3 Hz), 4.72 - 4.91 (1H, m), 8.03 (1H, s).

Example 72

Preparation of (R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl N-methyl-N- (4-trifluoromethoxybenzyl) carbamate [2025] (R) -2-chloro -1- (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole prepared in Example 10 (2.16 g, 9.18 mmol), Ν, Ν-diisopropylethylamine (2.67 ml, 15.30 mmol) and 4dimethylaminopyridine (0.19 g, 1.53 mmol) were added to a suspension of N-methyl-N- (4-trifluoromethoxybenzyl) carbamoyl chloride (2.05 g, 7.65 mmol) in toluene (40 ml) , followed by stirring at 100 ° C for 3.5 hours. The reaction mixture was diluted with ethyl acetate, and the solution washed with 10% hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving (R) -3- (2-) N- methyl-N- (4-trifluoromethoxybenzyl) carbamate chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl (2.74 g, 77% yield) as a colorless oil.

[2026] ¹ H NMR (CDCb) δ ppm:

[2027] 1.25 (3H, s), 2.83 (3H, s), 3.87 - 4.17 (4H, m), 4.44 (2H, s), 7.18 - 7.25 (4H,

m), 8.05 (1H, s).

Example 73

Preparation of (R) -2-methyl-6-nitro2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [2028] N-methyl-N- (4-trifluoromethoxybenzyl) carbamate [2028] sodium (0.28 g, 7.04 mmol) to a solution of (R) -3 (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl N-methyl-N- (4trifluoromethoxybenzyl ) carbamate prepared in Example 72 (2.74 g, 5.87 mmol) in DMF (20 ml), followed by stirring for 1 hour with cooling in an ice bath. Ice water was added to the reaction mixture, and the precipitates were removed

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547/854 porfiltration, washed with water and then recrystallized from isopropanol giving (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-N-methylN- (4-trifluoromethoxybenzyl) carbamate -ylmethyl (1.40 g, 55% yield) as a white solid.

[2029] Melting point 123-124 ° C

Example 74

Preparation of (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl N- (4-chlorophenyl) -N-cyclohexylcarbamate [2030] (R) -2-chloro-1 - (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole prepared in Example 10 (0.95 g, 4.03 mmol), N, N-diisopropylethylamine (1.45 ml, 8 , 06 mmol) and 4-dimethylaminopyridine (0.10 g, 0.81 mmol) to a suspension of N (4-chlorophenyl) -N-cyclohexylcarbamoyl chloride (1.56 g, 6.05 mmol) in toluene (10 ml), followed by stirring at 100 ° C for 3 hours. The reaction mixture was diluted with ethyl acetate, and the solution was washed with 10% hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2- hydroxy-2-methylpropyl-N- (4-chlorophenyl) N-cyclohexylcarbamate (0.75 g, 40% yield) as a white amorphous form. [2031] ¹ H NMR (CDCb) δ ppm:

[2032] 0.78 -1.22 (6H, m), 1.24 -1.48 (2H, m), 1.54-1.67 (1H, m), 1.70 -1.93 ( 4H,

m), 2.87-3.13 (1H, m), 3.72 -3.98 (3H, m), 4.00-4.24 (2H, m), 7.00-7.06 ( 2H, m), 7.35-7.41 (2H, m), 7.80 (1H, br).

Example 75

Preparation of (R) -2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [2033] N- (4-chlorophenyl) -N-cyclohexylcarbamate [2033] sodium (76 mg, 1.91 mmol) to a solution of (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy N- (4-chlorophenyl) -N-cyclohexylcarbamate -2 methylpropyl prepared in Example 74 (0.75 g, 1.59 mmol) in DMF (7 ml), followed by stirring for 0.5 hours with cooling in an ice bath. Ice water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then

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548/854 concentrated under reduced pressure. The residue was recrystallized from isopropanol giving (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl N- (4-chlorophenyl) -N-cyclohexylcarbamate (0 , 53 g, 77% yield) as a white solid.

[2034] Melting point 175-177 ° C

Example 76

Preparation of (R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl N-methyl-N- (4-trifluoromethoxyphenyl) carbamate [2035] N-methyl- N- (4-trifluoromethoxyphenyl) -carbamoyl chloride (1.33 g, 5.23 mmol), N, N-diisopropylethylamine (1.2 ml, 6.97 mmol) and 4-dimethylaminopyridine (85 mg, 0.70 mmol) to a suspension of (R) -2-chloro-1- (2,3-dihydroxy-2-methyl) propyl-4-nitroimidazole prepared in Example 10 (0.82 g, 3.48 mmol) in toluene (10 ml ), followed by stirring at 100 ° C for 5 hours. The reaction mixture was diluted with ethyl acetate, and the solution was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 2/1) giving N-methylN- (4-trifluoromethoxyphenyl) carbamate of (R) -3- (2-chloro- 4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl (1.04 g, 65% yield) as a light yellow amorphous form.

[2036] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[2037] 1.02 (3H, s), 3.26 (3H, s), 3.80 - 4.00 (4H, m), 5.39 (1H, s), 7.37 - 7.40 (2H,

m), 7.47 - 7.52 (2H, m), 8.25 (1H, s).

Example 77

Preparation of (R) -2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [N-methyl-N- (4-trifluoromethoxyphenyl) carbamate [2038] sodium (0.48 g, 11.9 mmol) to a solution of (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-Nmethyl-N- (4-trifluoromethoxyphenyl) carbamate -methylpropyl prepared in Example 76 (4.50 g, 9.94 mmol) in DMF (13.5 ml) with cooling in an ice bath, followed by stirring at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the precipitates were removed by filtration. The precipitates were recrystallized from isopropanol giving (R) -2-methyl-6-nitro N-methyl-N- (4-trifluorornethoxyphenyl) carbamate

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2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl (2.95 g, 71% yield) as a light yellow solid.

[2039] Melting point 144-145 ° C [2040] Optical purity 99.8% e.e.

[2041] [a] d ²⁴ = 7.68 ° (concentration: 0.938, CHCb) [2042] Using corresponding starting materials, compounds of Examples 78 and 79 were obtained in the same manner as in Example 77.

Example 78

(R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl methylcarbamate [2043] 26% yield, melting point 175-178 ° C

Example 79

(R) -2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [2044] yield 27%, melting point 196-197 ° C

Example 80

Preparation of (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [2045] N- (4-chlorophenyl) -N-methylcarbamate [2045] Iodomethane (0 , 71 ml, 11.4 mmol) and potassium hydroxide (0.64 g, 11.4 mmol) to a solution of (R) -3- (2-chloro-4-nitroimidazole-1-yl) 4-chlorophenylcarbamate - 2-hydroxy-2-methylpropyl prepared in Example 64 (1.5 g, 3.8 mmol) in DMSO (40 ml), followed by stirring at room temperature for 4 hours. The mixture was cooled in an ice bath and received the addition of 10% hydrochloric acid. The resulting mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (nhexane / ethyl acetate = 1/1) and recrystallized from isopropanol giving (R) -2-methyl-6nitro-2,3-dihydroimidazo [2,1- b] oxazol-2-ylmethyl N- (4-chlorophenyl) -N-methylcarbamate (0.67 g, 60%) as a white solid.

[2046] Melting point 131 -133 ° C [2047] Optical purity 99.8% e.e.

[2048] [a] d ²⁶ = 22.86 ° (concentration: 1.028, CHCb)

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Example 81

Preparation of (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl bis (4-chlorophenyl) carbamate [2049] Pyridine (0.37 ml, 4.5 mmol) and triphosgene (0.16 g, 0.5 mmol) to a suspension of (R) -2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 37 (0.30 g, 1.5 mmol) in methylene chloride (15 ml) with cooling in an ice bath, followed by stirring at room temperature for 2.5 hours. Bis (4-chlorophenyl) amine (0.39 g, 1.6 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was cooled in an ice bath and 10% hydrochloric acid was added. The resulting mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 19/1) and recrystallized from isopropanol giving (R) -2-methyl-6-nitro- (4) chloro-phenyl) carbamate 2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl (82 mg, 12% yield) as a white solid.

[2050] Melting point 200-201 ° C

Example 82

Preparation of 2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl pipehdino-1-carboxylate [2051] Pyridine (0.37 ml, 4.5 mmol) was added and triphosgene (0.18 g, 0.6 mmol) to a suspension of 2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 33 (0.3 g , 1.5 mmol) in methylene chloride (15 ml) with cooling in an ice bath, followed by stirring at room temperature for 2 hours. The reaction mixture was cooled in an ice bath and received the addition of piperidine (0.16 ml, 1.7 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled in an ice bath and received the addition of 10% hydrochloric acid, and insoluble materials were removed by filtration. The filtrate was extracted with methylene chloride, and the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was

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551/854 purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/2) and recrystallized from methylene chloride-diisopropyl ether giving piperidine-

1-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl carboxylate (65 mg, 14% yield) as a white solid.

[2052] Melting point 152-154 ° C

Example 83

Preparation of 3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl 4- (4-trifluoromethoxyphenyl) piperazine-1-carboxylate [2053] 4- (4- trifluoromethoxyphenyl) piperazine-1-carbonyl (0.26 g, 0.85 mmol), N, N-diisopropylethylamine (0.30 ml, 1.7 mmol) and 4-dimethylaminopyridine (21 mg, 0.17 mmol) to a suspension of 2-chloro-1 - (2,3-dihydroxy-

2-methylpropyl) -4-nitroimidazole prepared in Example 3 (0.30 g, 1.3 mmol) in toluene (5 ml), followed by stirring at 100 ° C for 2.5 hours. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 3- (2-chloro-4-nitroim idazole 4- (4trifluoromethoxyphenyl) piperazine-1-carboxylate -1 -yl) -2hydroxy-2-methylpropyl (0.24 g, 55% yield) as a light yellow oil.

[2054] ¹ H NMR (CDCb) δ ppm:

[2055] 1.26 (3H, s), 3.02 - 3.17 (4H, m), 3.39 - 3.72 (4H, m), 3.91 (1H, s), 3.99 4.18 (3H, m), 4.34 (1H, d, J = 12.3 Hz), 6.85 - 6.98 (2H, m), 7.09 - 7.22 (2H, m) , 8.05 (1H, s).

Example 84

Preparation of 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl 4- (4-trifluoromethoxyphenyl) piperazine-1-carboxylate [2056] Sodium hydride (23 mg , 0.56 mmol) to a solution of 3- (2-chloro-4-nitroimidazol-1-yl) -2hydroxy-2-methylpropyl 4- (4trifluoromethoxyphenyl) -piperazine-1-carboxylate prepared in Example 83 (0 , 24 g, 0.47 mmol) in DMF (2 ml), followed by stirring at 0 ° C for 1 hour. Ice water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed

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552/854 with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) and then washed with diisopropyl ether giving 2-methyl-6-nitro-2,3-4- (4trifluoromethoxyphenyl) piperazine-1-carboxylate dihydroimidazo [2,1b] oxazol-2-ylmethyl (0.13 g, 58% yield) as a white solid.

[2057] Melting point 138-140 ° C

Example 85

Preparation of 3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate [2058] if 2-chloro-1 - (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole prepared in Example 3 (0.13 g, 0.57 mmol), N, N-diisopropylethylamine (0.13 ml, 0 , 76 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) to a suspension of 4 (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carbonyl chloride (0.10 g, 0 , 38 mmol) in toluene (3 ml), followed by stirring at 100 ° C for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate 3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl (0.11 g, 59% yield) as a colorless oil.

[2059] ¹ H NMR (CDCb) δ ppm:

[2060] 1.26 (3H, s), 2.43 - 2.50 (2H, m), 3.50 - 3.78 (2H, m), 3.93 - 4.24 (5H, m) ,

7.46 (1H, d, J = 8.3 Hz), 7.60 (1H, d, J = 8.3 Hz), 8.05 (1H, s).

Example 86

Preparation of 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate [2061] Sodium hydride (11 mg, 0.28 mmol) was added to a solution of 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate 3- (2-chloro-4-nitroimidazole1 - il) -2-hydroxy-2-methylpropyl prepared in Example 85 (0.11 g, 0.23 mmol) in DMF (1 ml), followed by stirring for 1 hour with cooling in an ice bath.

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553/854

Ice water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 4/1) and then washed with diisopropyl ether giving 4- (4-trifluoromethylphenyl) -1,2,3,6tetrahydropyridine 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methylmethyl -1-carboxylate (0.04 g, 39% yield) as a white solid.

[2062] Melting point 113-115 ° C

Example 87

Preparation of (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl 4-tert-butoxycarbonylpiperazine-1-carboxylate [2063] (R) -2-chloro -1 - (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole prepared in Example 10 (4.43 g, 18.79 mmol), N, N-diisopropylethylamine (4.68 ml, 26.84 mmol) and 4-dimethylaminopyridine (0.33 g, 2.68 mmol) to a suspension of tert-butyl 4-chlorocarbonylpiperazine-1-carboxylate (3.34 g, 13.42 mmol) in toluene (70 ml), and the resulting mixture it was stirred at 100 ° C for 4.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / methylene chloride / ethyl acetate = 45/45/10) giving (R) -3- 4-ter-butoxycarbonylpiperazine-1-carboxylate (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl (4.12 g, 69% yield) as a colorless oil.

[2064] ¹ H NMR (CDCb) δ ppm:

[2065] 1.23 (3H, s), 1.47 (9H, s), 3.33 - 3.50 (8H, m), 3.91 (1H, s), 3.99 - 4.16 (3H,

m), 4.30 (1H, d, J = 12.1 Hz), 8.04 (1H, s).

[2066] Using 4- (4-trifluoromethoxybenzyloxycarbonyl) piperazine-1carbonyl chloride or 4- [3- (4-trifluoromethylphenyl) -2-propenyloxycarbonyl] piperazine-1carbonyl chloride, compounds of Examples 88 and 89 were obtained in the same way as in Example 87.

Example 88

Petition 870190039560, of 26/04/2019, p. 562/876

554/854 (R) -2-chloro-1 - {3- [4- (4-trifluoromethoxybenzyloxycarbonyl) piperazin-1-icarbon i loxy] -2hydroxy-2-methyl-propyl} -4-nitroimidazole [2067] yield 81% [2068] ¹ H NMR (CDCb) δ ppm:

[2069] 1.24 (3H, s), 3.28 - 3.61 (8H, m), 3.89 (1H, s), 4.00 - 4.20 (3H, m), 4.31 (1H, d, J = 12.5 Hz), 5.14 (2H, s), 7.22 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8, 7 Hz), 8.04 (1H, s).

Example 89 (R) -2-chloro-1- {3- [4- [3- (4-trifluoromethylphenyl) -2-propenylcarbonyl] piperazin-1ylcarbonyloxy] -2-hydroxy-2-methylpropyl} -4-nitroimidazole [2070 ] 95% yield [2071] ¹ H NMR (CDCb) δ ppm:

[2072] 1.24 (3H, s), 3.33 - 3.61 (8H, m), 3.90 (1H, s), 3.99 - 4.17 (3H, m), 4.31 (1H, d, J = 12.1 Hz), 4.79 (2H, d, J = 6.1 Hz), 6.39 (1H, dt, J = 6.1 Hz, 15.9 Hz), 6.67 (1H, d, J = 15.9 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3 Hz), 8, 04 (1H, s). Example 90

Preparation of (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl 4- (4-chlorobenzyl) piperazine-1-carboxylate [2073] (R) - 2-chloro-1 - (2,3-dihydroxy-2-methyl) propyl-4-nitroimidazole prepared in Example 10 (2.28 g, 9.66 mmol), Ν, Ν-diisopropylethylamine (2.81 ml, 16 , 10 mmol) and 4-dimethylaminopyridine (0.20 g, 1.61 mmol) to a suspension of 4 (4-chlorobenzyl) piperazine-1-carbonyl chloride (2.20 g, 8.05 mmol) in toluene ( 30 ml), followed by stirring at 100 ° C for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy- 2-methylpropyl 4- (4-chlorobenzyl) piperazine-1-carboxylate (1.82 g, 48% yield) as a yellow oil.

[2074] ¹ H NMR (CDCb) δ ppm:

[2075] 1.23 (3H, s), 2.17 - 2.50 (4H, m), 2.55 (1H, s), 3.26 - 3.52 (6H, m), 3.98

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555/854

4.20 (3H, m), 4.30 (1H, d, J = 12.4 Hz), 7.23 - 7.32 (4H, m), 8.05 (1H, s).

[2076] Using corresponding starting materials, compounds of Examples 91 and 92 were obtained in the same manner as in Example 90.

Example 91 (R) -2-chloro-1- {3- [4- (4-trifluoromethylbenzyl) piperazin-1-ylcarbonyloxy] -2-hydroxy-2methylpropyl} -4-nitroimidazole [2077] 31% yield [2078] ¹ H NMR (CDCb) δ ppm:

[2079] 1.23 (3H, s), 2.24 - 2.54 (4H, m), 3.24 - 3.50 (4H, m), 3.56 (2H, s), 3.97 4.20 (3H, m), 4.32 (1H, d, J = 12.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.58 (2H, d, J = 8.0 Hz), 8.05 (1H, s).

Example 92 (R) -2-chloro-1- {3- [4- (4-trifluoromethoxybenzyl) piperazin-1-ylcarbonyloxy] -2-hydroxy-2methylpropyl} -4-nitroimidazole [2080] 47% yield [2081] ¹ H NMR (CDCb) δ ppm:

[2082] 1.23 (3H, s), 2.22 - 2.54 (4H, m), 3.30 - 3.54 (4H, m), 3.50 (2H, s), 3.97 -

4.16 (3H, m), 4.32 (1H, d, J = 12.5 Hz), 7.15 - 7.18 (2H, m), 7.32 - 7.36 (2H, m) , 8.05 (1H, s).

Example 93

Preparation of (R) -3- (2-chloro-4nitroim idazol-1 -yl) -2-hydroxy-2-methylpropyl 4- (4-trifluoromethoxyphenyl) piperazine-1-carboxylate [2083] 4- (4) chloride -trifluoromethoxyphenyl) piperazine-1-carbonyl (1.25 g, 4.2 mmol), N, N-diisopropylethylamine (0.96 ml, 5.6 mmol) and 4-dimethylaminopyridine (67 mg, 0.56 mmol) a a suspension of (R) -2-chloro-1- (2,3-dihydroxy-2-methylpropyl) -4nitroimidazole prepared in Example 10 (0.65 g, 2.8 mmol) in toluene (13 ml), followed by stirring at 100 ° C for 8.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (methylene chloride / ethyl acetate = 19/1) giving 4- (4

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556/854 (R) -3- (2-chloro-4-nitroimidazole-1-yl) -2hydroxy-2-methylpropyl trifluoromethoxyphenyl) piperazine-1-carboxylate (1.29 g, 92% yield) as an oil yellow.

[2084] ¹ H NMR (CDCb) δ ppm:

[2085] 1.26 (3H, s), 3.02 - 3.17 (4H, m), 3.39 - 3.72 (4H, m), 3.91 (1H, s), 3.99 4.18 (3H, m), 4.34 (1H, d, J = 12.3 Hz), 6.85 - 6.98 (2H, m), 7.09 - 7.22 (2H, m) , 8.05 (1H, s).

[2086] Using corresponding starting materials, compounds of Examples 94 to 102 were obtained in the same manner as in Example 93.

Example 94

(R) -3- 4- (4-trifluoromethylphenyl) piperazine-1-carboxylate (2-chloro-4-nitroimidazol-1-yl) 2-hydroxy-2-methylpropyl [2087] 48% yield [2088] ¹ H NMR (CDCb) δ ppm:

[2089] 1.26 (3H, s), 3.13 - 3, 35 (4H, m), 3.48 - 3.72 (4H, m), 3.94 (1H, s), 4.00 4.18 (3H, m), 4.33 (1H, d, J = 12.3 Hz), 6.93 (2H, d, J = 8.6 Hz), 7.50 (2H, d, J = 8.6 Hz), 8.05 (1H, s).

Example 95

(R) -3- (2-chloro-4-nitroimidazole-1-yl) -2hydroxy-2-methylpropyl 4- (4-methoxyphenyl) piperazine-1-carboxylate [2090] 54% yield [2091] ¹ H NMR (CDCb) δ ppm:

[2092] 1.24 (3H, s), 2.93 - 3.09 (4H, m), 3.52 - 3.63 (4H, m), 3.77 (3H, s), 3.96 (1H,

s), 4.00-4.19 (3H, m), 4.32 (1H, d, J = 12.3 Hz), 6.82-6.92 (4H, m), 8.05 (1H , s).

Example 96

(R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl 4- (4-chlorophenyl) piperazine-1-carboxylate [2093] 81% yield [2094] ¹ H NMR (CDCb) δ ppm:

[2095] 1.25 (3H, s), 3.00 - 3.13 (4H, m), 3.52 - 3.65 (4H, m), 3.93 (1H, s), 4.00 -

4.17 (3H, m), 4.33 (1H, d, J = 12.5 Hz), 6.82-6.86 (2H, m), 7.20-7.25 (2H, m) , 8.05

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557/854 (1H, s).

Example 97

(R) -3- 4- (3-chlorophenyl) piperazine-1-carboxylate (2-chloro-4-nitroimidazol-1-yl) -2hydroxy-2-methylpropyl [2096] 87% yield [2097] ¹ H NMR (CDCb) δ ppm:

[2098] 1.25 (3H, s), 3.04 - 3.22 (4H, m), 3.43 - 3.70 (4H, m), 3.89 (1H, s), 4.00 -

4.17 (3H, m), 4.33 (1H, d, J = 12.3 Hz), 6.78 (1H, ddd, J = 1.6 Hz, 2.4 Hz, 8.4 Hz) , 6.85 -6.88 (2H, m), 7.19 (1H, t, J = 8.4 Hz), 8.05 (1H, s).

Example 98

(R) -3- (2-chloro-4-nitroimidazole-1-yl) -2hydroxy-2-methylpropyl 4- (3,4-dichlorophenyl) piperazine-1-carboxylate [2099] 47% yield [2100] ¹ H NMR (DMSO-de) δ ppm:

[2101] 1.12 (3H, s), 3.15 - 3.26 (4H, m), 3.39 - 3.61 (4H, m), 3.88 (1H, d, J = 11, 0

Hz), 3.93 (1H, d, J = 11.0 Hz), 4.07 (1H, d, J = 14.7 Hz), 4.15 (1H, d, J = 14.7 Hz) , 6.96 (1H, dd, J = 2.9 Hz, 9.1 Hz), 7.16 (1H, d, J = 2.9 Hz), 7.42 (1H, d, J = 9, 1 Hz), 8.34 (1H, s).

Example 99

(R) -3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl 4- (4-fluorophenyl) piperazine-1-carboxylate [2102] 100% yield [2103] ¹ H NMR (CDCb) δ ppm:

[2104] 1.25 (3H, s), 2.96 - 3.09 (4H, m), 3.50 - 3.67 (4H, m), 3.98 (1H, s), 4.05 4.16 (3H, m), 4.33 (1H, d, J = 12.3 Hz), 6.85 - 7.02 (4H, m), 8.05 (1H, s).

Example 100

(R) -3- (2-Chloro-4-nitroimidazol-1-yl) 4- (3-trifluoromethylphenyl) piperazine-1-carboxylate [2105] 83% yield [2106] ¹ H NMR (CDCb) δ ppm:

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558/854 [2107] 1.25 (3H, s), 3.11 - 3.26 (4H, m), 3, 48 - 3.70 (4H, m), 3.91 (1H, s), 4.00 4.24 (3H, m), 4.33 (1H, d, J = 12.3 Hz), 7.02 - 7.20 (3H, m), 7.38 (1H, t, J = 8.0 Hz), 8.05 (1H, s).

Example 101 (R) -2-chloro-1- (3-diethylaminocarbonyloxy-2-hydroxy-2-methylpropyl) -4-nitroimidazole [2108] 37% yield [2109] ¹ H NMR (CDCb) δ ppm:

[2110] 1.11 (6Η, t, J = 7.1 Hz), 1.20 (3H, s), 3.16 (4H, q, J = 7.1 Hz), 3.76 (1H, br),

4.06 - 4.11 (3H, m), 4.26 (1H, d, J = 11.1 Hz), 8.05 (1H, s).

Example 102 2-chloro-1- (3-morpholinocarbonyloxy-2-hydroxy-2-methylpropyl) -4-nitroimidazole [2111] 100% yield [2112] ¹ H NMR (CDCb) δ ppm:

[2113] 1.23 (3H, s), 3.35 - 3.52 (4H, m), 3.61 - 3.72 (4H, m), 3.99 - 4.16 (3H, m) ,

4.31 (1H, d, J = 12.3 Hz), 8.05 (1H, s).

Example 103

Preparation of (R) -3 (2) Chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl 4- (4-trifluoromethylbenzylideneamino) piperazine [2114] (R) -2-chloro-1- (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole prepared in Example 10 (2.75 g, 11.66 mmol), Ν, Ν-diisopropylethylamine (2.71 ml, 15 , 54 mmol) and 4-dimethylaminopyridine (0.19 g, 1.55 mmol) to a suspension of 4- (4-trifluoromethylbenzylidenoamino) piperazine-1-carbonyl chloride (2.48 g, 7.77 mmol) in toluene (40 ml), followed by stirring at 100 ° C for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 4- (4-trifluoromethylbenzylideneamino) piperazino-

(R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl 1-carboxylate (4.03 g, quantitative) as a yellow oil.

[2115] ¹ H NMR (CDCb) δ ppm:

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559/854 [2116] 1.25 (3H, s), 3.04 - 3.33 (4H, m), 3.48 - 3.76 (4H, m), 3.83 (1H, s), 4.00 -

4.17 (3H, m), 4.33 (1H, d, J = 12.3 Hz), 7.55 (1H, s), 7.59 (2H, d, J = 8.4 Hz), 7.69 (2H, d, J = 8.4 Hz), 8.04 (1H, s).

Example 104

Preparation of (R) -3- (2-chloro-4-nitroim idazol-1 -yl) -2-hydroxy-2-methylpropyl 4- (4-trifluoromethylphenoxy) pipendino-1-carboxylate [2117] (R) -2-chloro-1- (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole prepared in Example 10 (1.16 g, 4.68 mmol) and triethylamine (1.63 ml, 11.70 mmol) to a suspension of 4- (4-trifluoromethylphenoxy) pipendin-1-carbonyl chloride (0.72 g,

2.34 mmol) in toluene (40 ml), followed by stirring at 100 ° C for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 4- (4-trifluoromethylphenoxy) pipendino-1-carboxylate (R) -3- (2- chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl (184 mg, 16% yield) as a colorless oil.

[2118] ¹ H NMR (CDCb) δ ppm:

[2119] 1.24 (3H, s), 1.72 - 1.98 (4H, m), 3.33 - 3.67 (4H, m), 3.91 - 4.20 (3H, m) ,

4.24 - 4.39 (1H, m), 4.52 - 4.65 (1H, m), 6.96 (2H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8, 7 Hz), 8.05 (1H, s).

Example 105

Preparation of (R) -3- (2-chloro) 4- (4-trifluoromethylphenylamino) pipendino-1-carboxylate

4-nitroim idazol-1 -yl) -2-hydroxy-2-methylpropyl [2120] (R) -2-chloro-1- (2,3-dihydroxy-2-methylpropyl) -4-nitroimidazole was added in Example 10 (1.54 g, 7.01 mmol), N, N-diisopropylethylamine (1.63 ml, 9.34 mmol) and 4-dimethylaminopyridine (0.11 g, 0.93 mmol) to a chloride suspension of 4 (4-trifluoromethylphenylamino) pipendino-1-carbonyl (1.43 g, 4.67 mmol) in toluene (30 ml), followed by stirring at 100 ° C for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by means of chromatography

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560/854 column on silica gel (methylene chloride / ethyl acetate = 9/1) giving 4- (4trifluoromethylphenylamino) pipendino-1-(R) -3- (2-chloro-4-nitroimidazole-1-carboxylate) -il) -

2-hydroxy-2-methylpropyl (1.44 g, 61% yield) as a light yellow oil. [2121] ¹ H NMR (CDCb) δ ppm:

[2122] 1.25 (3H, s), 1.30 - 1.48 (2H, m), 1.98 - 2.13 (2H, m), 2.83 - 3.13 (2H, m) ,

3.37 - 3.61 (1H, m), 3.83 - 3.96 (2H, m), 3.96 - 4.22 (4H, m), 4.34 (1H, d, J = 11 , 8 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 8.07 (1H, s).

Example 106

Preparation of (R) -3 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl [2123] (R) -2-chloro-1- (2,3-dihydroxy-2-methyl) propyl-4-nitroimidazole prepared in Example 10 (0.74 g, 3.11 mmol) and triethylamine ( 1.74 ml, 12.42 mmol) to a suspension of 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1carbonyl chloride (0.60 g, 2.07 mmol) in toluene (36 ml), followed by stirring at 100 ° C for 16 hours. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-

(R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl 1-carboxylate (0.32 g, 31% yield) as a light yellow oil.

[2124] ¹ H NMR (CDCb) δ ppm:

[2125] 1.26 (3H, s), 2.43 - 2.50 (2H, m), 3.50 - 3.78 (2H, m), 3.93 - 4.24 (5H, m) ,

7.46 (2H, d, J = 8.3 Hz), 7.60 (2H, d, J = 8.3 Hz), 8.05 (1H, s).

[2126] Using corresponding starting materials, compounds of Examples 107 to 112 were obtained in the same manner as in Example 106.

Example 107

(R) -3- 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl [2127] 94% yield [2128] ¹ H NMR (CDCb) δ ppm:

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561/854 [2129] 1.25 (3H, s), 2.41 - 2.59 (2H, m), 3.50 - 3.78 (2H, m), 3.93 - 4.22 (6H , m),

4.35 (1H, d, J = 12.3 Hz), 5.87 - 6.13 (1H, m), 7.26 - 7.37 (4H, m), 8.05 (1H, s) . Example 108

(R) -3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl 4- (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate [2130 ] 92% yield [2131] ¹ H NMR (CDCb) δ ppm:

[2132] 1.26 (3H, s), 2.46 -2.59 (2H, m), 3.13 - 3.37 (1H, m), 3.50 - 3.74 (2H, m) ,

4.00 - 4.14 (6H, m), 4.36 (1H, d, J = 12.4 Hz), 7.19 (2H, d, J = 8.0 Hz), 7.37 (2H , d, J = 8.0 Hz), 8.05 (1H, s).

Example 109

(R) -3- (2-chloro-4-nitroim idazol-1 -yl) -2-hydroxy-2-methylpropyl 4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate [2133 ] 63% yield [2134] ¹ H NMR (CDCb) δ ppm:

[2135] 1.23 (3H, s), 2.43 - 2.61 (2H, m), 3.52 - 3.74 (2H, m), 3.82 (3H, s), 4.01 4.16 (5H, m), 4.34 (1H, d, J = 12.6 Hz), 5.83 - 6.00 (1H, m), 6.88 (2H, d, J = 8, 8 Hz), 7.30 (2H, d, J = 8.8 Hz), 8.05 (1H, s).

Example 110

(R) -3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate [2136 ] 54% yield [2137] ¹ H NMR (CDCb) δ ppm:

[2138] 1.25 (3H, s), 2.46 - 2.70 (2H, m), 3.50 - 3.78 (2H, m), 4.00 - 4.32 (6H, m) ,

4.35 (1H, d, J = 12.6 Hz), 5.98 - 6.22 (1H, m), 7.39 - 7.67 (4H, m), 8.06 (1H, s) . Example 111

(R) -3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl 4- (4-bromophenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate [2139 ] 80% yield [2140] ¹ H NMR (CDCb) δ ppm:

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562/854 [2141] 1.25 (3H, s), 2.41 - 2.63 (2H, m), 3.50 - 3.76 (2H, m), 3.96 - 4.20 (6H , m),

4.35 (1H, d, J = 12.3 Hz), 5.87 - 6.13 (1H, m), 7.15-7.26 (2H, m), 7.43-7.48 ( 2H, m), 8.05 (1H, s).

Example 112

(R) -3- 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate (2-chloro-4-nitroim idazol-1 -yl) -2-hydroxy-2-methylpropyl [2142] 57% yield [2143] ¹ H NMR (CDCb) δ ppm:

[2144] 1.25 (3H, s), 2.41 - 2.63 (2H, m), 3.50 - 3.76 (2H, m), 3.89 - 4.22 (6H, m) ,

4.35 (1H, d, J = 12.6 Hz), 5.83 - 6.04 (1H, m), 6.99 - 7.06 (2H, m), 7.29 - 7.35 ( 2H, m), 8.05 (1H, s).

[2145] Using 5-chloro-2,3-dihydroindol-1-carbonyl chloride, 5-chloro-chloride

I, 3-dihydroisoindol-2-carbonyl, 6-chloro-3,4-dihydro-1 H-isoquinoline-2-carbonyl chloride or 6-chloro-3,4-dihydro-2H-quinoline-1-carbonyl chloride were made up of Examples 113 to 116 in the same way as in Example 106. Example 113

5- (R) -3- (2-chloro-4-nitroim idazol-1-yl) -2-h idroxy-2-methylpropyl chloroindole ini 1-1 -carboxylate [2146] Light yellow amorphous form, yield 50 % [2147] ¹ H NMR (CDCb) δ ppm:

[2148] 1.27 (3H, s), 3.14 (2H, t, J = 8.5 Hz), 3.42 (1H, br), 3.91 - 4.28 (5H, m), 4.37 (1H, d, J = 11.8 Hz), 7.04 - 7.24 (2H, m), 7.73 (1H, d, J = 8.3 Hz), 8.04 (1H , s).

Example 114

(R) -3- (2-chloro-4-nitroim idazol-1-yl) -2-h idroxy-2methylpropyl 5-chloroisoindolinyl-2-carboxylate [2149] Brown solid, 19% yield [2150] ¹ H NMR (CDCb) δ ppm:

[2151] 1.27 (3H, s), 3.93 (1H, d, J = 7.8 Hz), 4.04 - 4.24 (7H, m), 4.32 (1H, d, J =

II, 8 Hz), 7.16 - 7.29 (3H, m), 8.07 (1H, s).

Example 115

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563/854

(R) -3- (2-chloro-4-nitroimidazol-1-yl) 6-chloro-3,4-dihydro-1-H-isoquinoline-2-carboxylate -

2-hydroxy-2-methylpropyl [2152] Light yellow oil, 63% yield [2153] ¹ H NMR (CDCb) δ ppm:

[2154] 1.24 (3H, s), 2.83 (2H, t, J = 5.8 Hz), 3.46 - 3.76 (2H, m), 3.90 (1H, d, J =

5.3 Hz), 4.01 -4.15 (3H, m), [2155] 4.34 (1H, d, J = 12.3 Hz), 4.43 - 4.65 (2H, m) , 6.93 - 7.09 (1H, m), 7.09 7.22 (2H, m), 8.04 (1H, s).

Example 116

(R) -3- (2-chloro-4-nitroimidazole-1-yl) -2hydroxy-2-methylpropyl 6-chloro-3,4-dihydro-2H-quinoline [2156] Light yellow oil, 70% yield [2157] ¹ H NMR (CDCb) δ ppm:

[2158] 1.26 (3H, s), 1.87 - 2.00 (2H, m), 2.76 (2H, t, J = 6.5 Hz), 3.27 (1H, br), 3.57

-3.83 (2H, m), 3.98-4.17 (3H, m), 4.33 (1H, d, J = 12.0 Hz), 7.12-7.16 (2H, m ), 7.41 -7.61 (1H, br), 7.98 (1H, s).

Example 117

Preparation of (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl 4-tert-butoxycarbonylpiperazine-1-carboxylate [2159] (R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl tert-butoxycarbonylpiperazine-1-carboxylate prepared in Example 87 (4.12 g, 9.20 mmol) in DMF (30 ml), sodium hydride (0.44 g, 11.04 mmol), followed by stirring for 1 hour with cooling in an ice bath. Water with ice was added to the reaction mixture, and the precipitates were removed by filtration, purified by column chromatography on silica gel (ethyl acetate) and then washed with isopropanol giving 4-ter-butoxycarbonylpiperazine-1-carboxylate of (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl (2.24 g, 59% yield) as a white solid.

[2160] Melting point 211-212 ° C.

Example 118

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564/854

Preparation of (R) -2-methyl-6-nitro- 4- (4-trifluoromethoxyphenyl) piperazine-1-carboxylate

2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [2161] (R) -3- (2-chloro-) 4- (4-trifluoromethoxyphenyl) piperazine-1-carboxylate solution was added to the solution 4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl prepared in Example 93 (1.29 g, 2.5 mmol) in DMF (13 ml), sodium hydride (0.12 g, 3 mmol) , followed by stirring for 1 hour with cooling in an ice bath. Water with ice was added to the reaction mixture, and the precipitates were removed by filtration, washed with water and recrystallized from isopropanol giving 4- (4) -trifluoromethoxyphenyl) (R) -2-methyl-6-nitro 4- (4-trifluoromethoxyphenyl) piperazine -2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl (0.70 g, 59% yield) as a white solid.

[2162] Optical purity 99.6% e.e.

[2163] [a] d ²⁵ = 0.99 ° (concentration: 0.704, CHCb) [2164] Melting point 168-169 ° C.

Example 119

Preparation of 4- (4-chlorobenzyl) piperazine-1-carboxylate from (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [2165] Added to the solution (R) - 4- (4-chlorobenzyl) piperazine-1-carboxylate

3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl prepared in Example 90 (1.82 g, 3.85 mmol) in DMF (10 ml), sodium hydride (0 , 31 g, 7.70 mmol), followed by stirring for 1 hour with cooling in an ice bath. Ice water was added to the reaction mixture, and the precipitates were removed by filtration and washed with isopropanol giving (R) -2-methyl-6nitro-2,3- 4- (4-chlorobenzyl) piperazine-1-carboxylate dihydroimidazo [2,1-b] oxazol-2-ylmethyl (0.46 g, 28% yield) as a light yellow solid.

[2166] Melting point 161-163 ° C.

Example 120

Preparation of (R) -2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl 4- (4-trifluoromethylbenzylideneamino) piperazine [2,167] was added to the solution (R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl 4- (4-trifluoromethylbenzylidenoamino) piperazino1-carboxylate

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565/854 in Example 103 (4.03 g, 7.77 mmol) in DMF (20 ml), sodium hydride (0.37 g, 9.32 mmol), followed by stirring for 1 hour with cooling in a water bath. ice. Water and ice were added to the reaction mixture, and the precipitates were removed by filtration, washed with water and recrystallized from acetonitrile-isopropanol giving (R) -2-methyl-4-4-4-trifluoromethylbenzylideneamino) piperazine-1-carboxylate 6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl (2.60 g, 69% yield) as a white solid.

[2168] Melting point 176-178 ° C.

Example 121

Preparation of (R) -2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl 4- (4-trifluoromethylphenylamino) pipendino-1-carboxylate [2169] (R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl 4- (4-trifluoromethylphenylamino) piperidine-1 carboxylate prepared in Example 105 (1.44 g, 2.85 mmol) in DMF (10 ml), sodium hydride (0.14 g, 3.42 mmol), followed by stirring for 1 hour with cooling in an ice bath. Ice water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) and recrystallized from acetonitrilaisopropanol giving 4- (4) trifluoromethylphenylamino) (R) -2methyl-6-nitro-2,3-pipendino-1-carboxylate -dihydroimidazo [2,1-b] oxazol-2-ylmethyl (0.42 g, 31% yield) as a white solid.

[2170] Melting point 137-140 ° C.

Example 122

Preparation of (R) -2-methyl-6-nitro- 4- (4-trifluoromethylphenoxy) pipendino-1-carboxylate

2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [2171] (R) -3- (2-chloro-) 4- (4-trifluoromethylphenoxy) piperidine-1-carboxylate solution was added to the solution 4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl prepared in Example 104 (0.18 g, 0.36 mmol) in DMF (2 ml), sodium hydride (19 mg, 0.47 mmol) , followed by stirring for 1.5 hours with cooling in an ice bath. Water was added

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566/854 with ice to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) and recrystallized from isopropanol giving 4- (4) -trendluoromethylphenoxy-pipendino-1-carboxylate (R) -2 -methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl (0.08 g, 47% yield) as a white solid.

[2172] Melting point 165-166 ° C.

Example 123

Preparation of 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine-1-carboxylate of (R) -2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2- ilmethyl [2173] (R) -3- (2-chloro-4-nitroimidazole-1-yl) 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine1-carboxylate - 2-hydroxy-2-methylpropyl prepared in Example 106 (0.32 g, 0.65 mmol) in DMF (3 ml), sodium hydride (31 mg, 0.78 mmol), followed by stirring for 1.5 hours with cooling in an ice bath. Ice water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) and recrystallized from isopropanol giving 4- (4-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine- 1 (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl carboxylate (0.14 g, 49% yield) as a white solid.

[2174] Optical purity 98.4% e.e.

[2175] [a] d ²⁶ = 2.50 ° (c0.560, CHCb).

[2176] Melting point 169-171 ° C.

Example 124

Preparation of (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl 5-chloro-2,3-dihydroindol-1-carboxylate [2177] (R) -3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl 5-chloro-2,3-dihydroindol-1-carboxylate solution prepared in Example 113 (0.60 g ,

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1.44 mmol) in DMF (6 ml), sodium hydride (70 mg, 1.73 mmol), followed by stirring 1 hour with cooling in an ice bath. Water with ice was added to the reaction mixture, and the precipitates were removed by filtration, washed with water and recrystallized from acetonitrile-isopropanol giving (R) -2-methyl 5-chloro-2,3-dihydroindol-1-carboxylate -6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl (0.30 g, 55% yield) as a white solid.

[2178] Melting point 189-191 ° C.

Example 125

Preparation of (R) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl 5-chloro-1,3-dihydroisoindol-2-carboxylate [2179] (R) - 5-chloro-1,3-dihydro-isoindol-2-carboxylate solution

3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl prepared in Example 114 (0.13 g, 0.31 mmol) in DMF (2 ml), sodium hydride (15 mg, 0.37 mmol), followed by stirring for 1 hour with cooling in an ice bath. Ice water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) giving (R) -2methyl-6-nitro-2,3-dihydroimidazo 5-chloro-1,3-dihydroisoindol [2 , 1-b] oxazol-2-ylmethyl (7 mg, 6% yield) as a light yellow solid.

[2180] Melting point 182 ° C (decomposition).

Example 126

Preparation of (R) -2-methyl-6-nitro- 6-chloro-3,4-dihydro-1 H-isoquinoline-2-carboxylate

2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl [2181] To the solution of (R) -3 6-chloro-3,4-dihydro-1 H-isoquinoline-2-carboxylate - (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl prepared in Example 115 (0.26 g, 0.61 mmol) in DMF (2 ml), sodium hydride (30 mg , 0.73 mmol), followed by stirring for 1 hour with cooling in an ice bath. Ice water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, concentrated under

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568/854 reduced pressure and recrystallized from isopropanol giving (R) -2-methyl-6-nitro-2,3-dihydroimidazo 6-chloro-3,4-dihydro-1-hyisoquinoline-2-carboxylate [2,1-b ] oxazole-2-methyl (0.12 g, 49%) as a light yellow solid.

[2182] Melting point 180-182 ° C.

Example 127

Preparation of (R) -2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl 6-chloro-3,4-dihydro-2H-quinoline-1-carboxylate [2183] (R) -3- (2-Chloro-4-nitroimidazol-1-yl) -2-hydroxy-2- 6-chloro-3,4-dihydro-2H-quinoline-1-carboxylate was added to the solution methylpropyl prepared in Example 116 (1.84 g, 4.29 mmol) in DMF (10 ml), sodium hydride (0.21 g, 5.15 mmol), followed by stirring for 1 hour with cooling in an ice bath . Ice water was added to the reaction mixture, the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) and recrystallized from acetonitrilaisopropanol giving 6-chloro-3,4-dihydro-2H-quinoline-1-carboxylate (R) -2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl (0.68 g, 40% yield) as a white solid.

[2184] Melting point 172-174 ° C.

Example 128

Preparation of 2-methyl-6-nitro-2- (4-trifluoromethoxyphenoxymethyl) -2,3-dihydroimidazo [2,1b] oxazol [2185] 4-Trifluoromethoxyphenol (198 mg, 1.11 mmol) was dissolved in DMF (5 ml). Sodium hydride (48 mg, 1.21 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 80 ° C. To the resulting solution, 2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (220 mg, 1.01 mmol) was added with cooling in an ice bath, and the solution was stirred for 15 minutes at 80 ° C. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was

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569/854 concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and then crystallized from methylene chloride-diisopropyl ether giving 2-methyl-6-nitro-2- ( 4trifluoromethoxyphenoxymethyl) -2,3-dihydroimidazo [2,1-b] oxazole (170 mg, 47% yield) as a white powder.

[2186] Melting point 126.8-127.9 ° C [2187] MS 358 (M-1) ⁺

Example 129

Preparation of 2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) piperidin-1 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole [2188] 4- [ 4- (4-trifluoromethoxyphenoxy) piperidin] -1-ylphenol (244 mg, 0.69 mmol) was dissolved in DMF (10 ml). Sodium hydride (33 mg, 0.83 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 80 ° C. To the solution, 2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (150 mg, 0.69 mmol) was added with cooling in an ice bath, and the solution was stirred at 80 ° C for 20 minutes. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and then crystallized from methylene chloride / ethyl acetate giving 2-methyl-6nitro-2- {4- [4- (4-thfluoromethoxyphenoxy) pipehdin-1-yl] phenoxymethyl} -2,3-dihydroimidazo [2,1b] oxazole (103 mg, 28% yield) as a white powder.

[2189] Melting point 165.4-166.3 ° C.

Example 130

Preparation of 2-methyl-6-nitro-2- {4- [4- (4-thfluoromethylphenyl) piperazin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole [2190] 4- [4- (4-thfluoromethylphenyl) piperazin-1-yl] phenol (296 mg, 0.92 mmol) was dissolved in DMF (10 ml) . Sodium hydride (44 mg, 1.1 mmol) was added to the solution

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570/854 at room temperature, and the solution was stirred for 20 minutes at 80 ° C. 2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (200 mg, 0.92 mmol) was added to the solution with cooling in an ice bath, and the solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and then crystallized from methylene chloride / ethyl acetate giving 2-methyl-6nitro-2- {4- [4- (4-trifluoromethylphenyl) piperazin-1-yl] phenoxymethyl} -2,3-dihydroimidazo [2,1b] oxazole (178 mg, 38% yield) as a white powder.

[2191] Melting point 230.7-233.1 ° C.

Example 131

Preparation of ter-butyl 4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate [2192] 4- (4 tert-butyl-hydroxyphenyl) piperazine-1-carboxylate (2.01 g, 7.23 mmol) was dissolved in DMF (20 ml). Sodium hydride (320 mg, 8 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 70 ° C. To the solution 2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (1.5 g, 7.23 mmol) was added with cooling in an ice bath, and the solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) and then crystallized from methylene chloride / ethyl acetate giving 4- [4- (2-methyl-6 -nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methylmethoxy) phenyl] terp-butyl piperazine-1-carboxylate (1.5 g, 45% yield) as

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571/854 a white powder.

[2193] ¹ H NMR (CDCb) δ ppm:

[2194] 1.48 (9H, s), 1.77 (3H, s), 2.99 - 3.03 (4H, m), 3.55 - 3.59 (4H, m), 4.02 (1H, d, J = 10.2 Hz), 4.04 (1H, d, J = 10.1 Hz), 4.18 (1H, d, J = 10.1 Hz), 4.49 (1H , d, J = 10.2 Hz), 6.76 - 6.81 (2H, m), 6.84 - 6.89 (2H, m), 7.55 (1H, s).

[2195] Melting point 212.0-214.5 ° C [2196] MS 459 (M ⁺ ).

Example 132

Preparation of tert-butyl 4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperidine-1-carboxylate [2197] 4- (4 tert-butyl-hydroxyphenyl) piperidine-1-carboxylate (364 mg, 1.31 mmol) was dissolved in DMF (10 ml). Sodium hydride (58 mg, 1.44 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 80 ° C. 2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (300 mg, 1.38 mmol) was added to the solution with cooling in an ice bath, followed by stirring for a further 20 minutes. minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and then crystallized from methylene chloride-diisopropyl ether giving 4- [4- (2-methyl-6-nitro) -2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] terp-butyl-1-carboxylate (248 mg, 41% yield) as a white powder.

[2198] Melting point 207.8-209.1 ° C.

Example 133

Preparation of 3,4-dichlorobenzyl 4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate [2199] 4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole-2Petition 870190039560, from 26/04/2019, page 580/876

572/854 ylmethoxy) phenyl] terp-butyl piperazine-1-carboxylate prepared in Example 131 (118 mg, 0.26 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and received the addition of methylene chloride (2 ml) and triethylamine (2 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in DMF (15 ml) and the solution received the addition of a solution of 3,4-dichlorobenzyl alcohol (136 mg, 0.77 mmol) and 1,1'-carbonyldiimidazole (125 mg, 0.77 mmol) in DMF (5 ml) stirred at room temperature for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving 4- [4- (2-methyl-6-nitro- 2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperazine-1-carboxylate of 3,4dichlorobenzyl (101 mg, 70% yield) as a light yellow powder.

[2200] ¹ H NMR (CDCb) δ ppm:

[2201] 1.77 (3H, s), 3.01 -3.06 (4H, m), 3.62-3.67 (4H, m), 4.02 (1H, d, J = 10, 2

Hz), 4.04 (1H, d, J = 10.2 Hz), 4.18 (1H, d, J = 10.2 Hz), 4.49 (1H, d, J = 10.2 Hz) , 5.09 (2H, s), 6.76-6.81 (2H, m), 6.84-6.89 (2H, m), 7.18-7.22 (1H, m), 7 , 41 -7.47 (2H, m), 7.55 (1H, s).

Example 134

Preparation of 2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylbenzyl) piperazin-1-yl] phenoxymethyl} -

2,3-dihydroimidazo [2,1-b] oxazole [2202] 4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazino- Tert-Butyl 1-carboxylate prepared in Example 131 (88 mg, 0.19 mmol) was dissolved in trifluoroacetic acid (5 ml), and the solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and received the addition of methylene chloride (2 ml) and triethylamine (2 ml).

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The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in dichloroethane and received the addition of 4-trifluoromethylbenzaldehyde (40 μΙ, 0.29 mmol) and sodium triacetoxyborohydride (82 mg, 0.38 mmol) with cooling in an ice bath, followed by stirring at room temperature. overnight. A saturated solution of sodium hydrogen carbonate and methylene chloride was added to the solution. The mixture was extracted with methylene chloride, and the organic phase was dried over magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-ethyl acetate giving 2-methyl-6-nitro-2- {4- [ 4- (4-trifluoromethylbenzyl) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole (53 mg, 53% yield) as a white powder.

[2203] Melting point 171.8-173.1 ° C.

[2204] Using tert-butyl 4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperidine-1-carboxylate prepared in Example 132 the compound of Example 135 in the same manner as in Example 134. Example 135 2-methyl-6-nitro-2- {4- [1- (4-trifluoromethoxybenzyl) pipendin-4-yl] phenoxymethyl} -2,3dihydroimidazo [ 2,1-b] oxazole [2205] 45% yield, melting point 160.6-161.1 ° C.

Example 136

Preparation of (R) -2-methyl-6-nitro-2- (4-trifluoromethoxyphenoxymethyl) -2,3 dihydroimidazo [2,1-b] oxazol [2206] 4-Trifluoromethoxyphenol (1.1 g, 6.17 mmol) was dissolved in DMF (20 ml). Sodium hydride (260 mg, 6.45 mmol) was added to the solution at room temperature, and the solution was stirred for 15 minutes at 80 ° C. To the solution (R) -2-chloro1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (1.22 g, 5.61 mmol) was added with cooling in an ice bath, and The solution was stirred for an additional 2 hours at 80 ° C. The reaction mixture was poured into ice water, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with

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574/854 water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and then crystallized from methylene chloride-diisopropyl ether giving (R) -2-methyl-6nitro-2 - (4-trifluoromethoxyphenoxymethyl) -2,3-dihydroimidazo [2,1-b] oxazole (1.03 g, 51% yield) as a white powder.

[2207] Optical purity> 99% e.e.

[2208] [a] d ²⁸ = 7.67 ° (concentration: 1.030, CHCb) [2209] MS 359 (M ⁺ ) [2210] Melting point 176.5-178.0 ° C.

[2211] Using corresponding starting materials, compounds of Examples 137 to 139 were obtained in the same manner as in Example 136.

Example 137 (R) -2-methyl-6-nitro-2- [4- (thiomorpholin-4-yl) phenoxymethyl] -2,3-dihydroimidazo [2,1-b] oxazole [2212] 38% yield, melting point 227.5-229.0 ° C, MS 376 (M ⁺ ).

Example 138 (R) -2-methyl-6-nitro-2- [4- (imidazol-1-yl) phenoxymethyl] -2,3-dihydroimidazo [2,1-b] oxazole [2213] yield of 44%, melting point 172-175 ° C.

Example 139 (R) -2-methyl-6-nitro-2- [4- (1,2,4-triazol-1-yl) phenoxymethyl] -2,3-dihydroimidazo [2,1-b] oxazole [2214 ] 53% yield, melting point 236.0-238.7 ° C.

[2215] Using ethyl 1- (4-hydroxyphenyl) piperidine-4-carboxylate, the compound of Example 140 was obtained in the same manner as in Example 136.

Example 140 (R) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperidine-4carboxylate [2216] yield 30%, melting point 208.2-211.5 ° C.

Example 141

Preparation of (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) pipendin-1

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575/854 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1 -b] oxazol [2217] 4- [4- (4-trifluoromethoxyphenoxy) piperidin-1-yl] phenol (17.4 g, 49.0 mmol) was dissolved in DMF (150 ml). Sodium hydride (2.15 g, 53.8 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 80 ° C. To the solution (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (14.9 g, 68.6 mmol) was added with cooling in an ice bath, and the solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the mixture was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and then crystallized from methylene chloride / ethyl acetate giving (R) -2-methyl-6-nitro -2- {4- [4- (4trifluoromethoxyphenoxy) pipendin-1-yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole (14.3 g, 55% yield) as a light yellow powder .

[2218] MS 535 (M + 1) ⁺ [2219] Optical purity 99.9% ee

[2220] [a] d ²⁸ = -9.94 ° (concentration: 1.006, CHCb) [2221] Melting point 194.5-196 ° C [2222] ¹ H NMR (CDCb) δ ppm:

[2223] 1.77 (3H, s), 1.87 -2.00 (2H, m), 2.05-2.16 (2H, m), 2.95 - 3.05 (2H, m) ,

3.32-3.41 (2H, m), 4.02 (1H, d, J = 10.2 Hz), 4.04 (1H, d, J = 10.2 Hz), 4.18 (1H , d, J = 10.2 Hz), 4.36-4.45 (1H, m), 4.49 (1H, d, J = 10.2 Hz), 6.74-6.81 (2H, m), 6.87 6.94 (4H, m), 7.11 - 7.16 (2H, m), 7.55 (1H, s).

Example 142

Preparation of (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenyl) piperazin-1 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole [2224 ] 4- [4- (4-trifluoromethoxyphenyl) piperazin-1-yl] phenol (1.7 g, 5.02 mmol) was dissolved in DMF (20 ml). Sodium hydride (221 mg, 5.53

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576/854 mmol) at room temperature, and the solution was stirred for 20 minutes at 80 ° C. To the solution (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (1.2 g, 5.53 mmol) was added with cooling in an ice bath, and the solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and then recrystallized from ethyl acetate giving (R) -2-methyl-6-nitro-2- { 4- [4- (4-trifluoromethoxyphenyl) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole (1.02 g, 39% yield) as a light yellow powder. [2225] MS 519 (M ⁺ ) [2226] Optical purity> 99% ee

[2227] [a] d ²⁸ = -18.02 ° (concentration: 1.160, CHCb) [2228] Melting point 262.5-265 ° C.

Example 143

Preparation of ter-butyl (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperidine-1-carboxylate [2229] Ter-butyl 4- (4-hydroxyphenyl) piperidine-1-carboxylate (1.07 g, 3.86 mmol) was dissolved in DMF (10 ml). Sodium hydride (185 mg, 4.63 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 80 ° C. To the solution (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (923 mg, 4.24 mmol) was added with cooling in an ice bath, and The solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel

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577/854 (methylene chloride / methanol = 200/1) and then crystallized from ethyl acetate-diisopropyl ether giving (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [ 2,1-b] oxazol-2ylmethoxy) phenyl] piperidine-1-carboxylate tert-butyl (857 mg, 48% yield) as a white powder.

[2230] MS 458 (M ⁺ ) [2231] Optical purity> 99% ee

[2232] [a] d ²⁸ = -1.07 ^o (concentration: 1.028, CHCb) [2233] Melting point 227.5-228.3 ° C (decomposition).

[2234] Using corresponding starting materials, the compound of Example 144 was obtained in the same manner as in Example 143.

Example 144 (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] -1,2,3,6tetrahydropyridine-1 tert-butyl carboxylate [2235] Melting point 183.0-189.0 ° C (decomposition).

Example 145

Preparation of ter-butyl (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) benzoyl] piperazine-1-carboxylate [2236] Ter-butyl 4- (4-hydroxybenzoyl) piperazine-1-carboxylate (6.6 g, 21.5 mmol) was dissolved in DMF (50 ml). Sodium hydride (991 mg, 24.8 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 80 ° C. To the solution (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (5.16 mg, 23.7 mmol) was added with cooling in an ice bath, and the solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water, dissolved in methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and then crystallized from methylene chloride-diisopropyl ether giving (R) -4- [4- (2-methyl -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole-2

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578/854 ylmethoxy) benzoyl] terp-butyl piperazine-1-carboxylate (7.35 g, 70% yield) as a white powder.

[2237] MS 488 (M + 1) ⁺ [2238] Melting point 222.5-224.0 ° C.

Example 146

Preparation of tertiary (R) -4- [2-chloro-4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate butyl [2239] ter-butyl 4- (2-chloro-4-hydroxyphenyl) piperazine-1-carboxylate (2.7 g, 8.63 mmol) was dissolved in DMF (20 ml). Sodium hydride (397 mg, 9.92 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 80 ° C. To the solution (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (2.1 g, 9.50 mmol) was added with cooling in an ice bath, and the solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and then crystallized from methylene chloride-ethyl acetate giving (R) -4- [2-chloro-4- (2 -methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethoxy) phenyl] piperazine-1-carboxylate (2.34 g, 55% yield) as a white powder.

[2240] MS 493 (M ⁺ ) [2241] Melting point 207.0-209.5 ° C.

Example 147

Preparation of ter-butyl (R) -4- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate [2242] Ter-butyl 4- (3-hydroxyphenyl) piperazine-1-carboxylate (3.23 g, 11.6 mmol) was dissolved in DMF (40 ml). Sodium hydride (557 mg, 13.9 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 80 ° C.

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579/854

To the solution (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (2.78 g, 12.8 mmol) was added with cooling in a water bath. ice, and the solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and then crystallized from methylene chloride ethyl acetate giving (R) -4- [3- (2-methyl-6 -nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] terp-butyl-1-carboxylate (1.4 g, 26% yield) as a white powder.

[2243] MS 459 (M ⁺ ) [2244] Melting point 179.5-182.0 ° C.

Example 148

Preparation of ter-butyl (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate [2245] Ter-butyl 4- (4-hydroxyphenyl) piperazine-1-carboxylate (13.5 g, 48.8 mmol) was dissolved in DMF (100 ml). Sodium hydride (2.15 g, 53.7 mmol) was added to the solution at room temperature, and the solution was stirred for 20 minutes at 70 ° C. To the solution (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (10.6 g, 48.8 mmol) was added with cooling in an ice bath , and the solution was stirred for another 20 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and then crystallized from methylene chloride ethyl acetate giving (R) -4- [4- (2-methyl-6 -nitro-2,3-dihydroimidazo [2,1-b] oxazol-2

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580/854 ylmethoxy) phenyl] terp-butyl piperazine-1-carboxylate (9.9 g, 44% yield) as a white powder.

[2246] Optical purity> 99.5% e.e.

[2247] [oc] d ²⁸ = -10.85 ° (concentration: 1.014, CHCb) [2248] MS 459 (M ⁺ ) [2249] Melting point 230-232 ° C [2250] ¹ H NMR (CDCb) δ ppm:

[2251] 1.48 (9H, s), 1.76 (3H, s), 2.99 - 3.03 (4H, m), 3.54 - 3.59 (4H, m), 4.02 (1H, d, J = 10.2 Hz), 4.04 (1H, d, J = 10.1 Hz), 4.18 (1H, d, J = 10.1 Hz), 4.49 (1H , d, J = 10.2 Hz), 6.76 - 6.81 (2H, m), 6.85 - 6.89 (2H, m), 7.58 (1H, s).

Example 149

Preparation of (R) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine dihydrochloride [2252] (R) -4- [4 - tert-butyl (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate prepared in Example 148 (300 mg, 0.65 mmol) it was dissolved in trifluoroacetic acid (5 ml), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol. Saturated hydrogen chloride (5 ml) in ethyl acetate was added to the solution, and the precipitates were filtered off and dried under reduced pressure giving (R) - [4 (2-methyl-6-nitro-2 dihydrochloride) , 3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperazine (279 mg, 99% yield) as a light yellow powder.

[2253] MS 359 (M ⁺ ) [2254] Melting point 212-220 ° C (decomposition) [2255] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[2256] 1.67 (3H, s), 3.22 - 3.31 (8H, m), 4.18 (1H, d, J = 10.9 Hz), 4.23 (2H, s),

4.37 (1H, d, J = 10.9 Hz), 6.85 (2H, d, J = 9.1 Hz), 7.00 (2H, d, J = 9.1 Hz), 8, 16 (1H, s), 9.37 (3H, br).

Example 150

Preparation of (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylbenzyl) piperazin-1

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581/854 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1 -b] oxazole [2257] A mixture of (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo Ter-butyl [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate prepared in Example 148 (800 mg, 1.74 mmol) and trifluoroacetic acid (3 ml) was stirred at room temperature for 7 hours . The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). Triethylamine (3 ml, 21.52 mmol) was added to the solution, followed by stirring at room temperature for 5 minutes. The mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-trifluoromethylbenzaldehyde (910 mg, 5.23 mmol), sodium cyanotrihydroborate (328 mg, 5.23 mmol) and acetic acid (0.33 ml, 5.23 mmol) were added, followed by stirring at temperature overnight. A saturated solution of sodium hydrogen carbonate and methylene chloride was added to the reaction mixture, and the solution was stirred and then extracted with methylene chloride. The organic phase was dried over magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) giving (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylbenzyl ) piperazin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole (667 mg, 74% yield) as a light yellow powder.

[2258] Melting point 205.5-207 ° C.

Example 151

Preparation of ethyl (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate [2259] (R ) Tert-butyl -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate prepared in Example 148 (300 mg , 0.65 mmol) in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and then methylene chloride (5 ml), triethylamine (2 ml) and ethyl chloroformate (0.11 ml, 1.31 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with methylene chloride. The organic phase was

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582/854 washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving (R) -4- [4- (2-methyl- Ethyl 6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methylmethoxy) phenyl] piperazine-1-carboxylate (182 mg, 65% yield) as a white powder.

[2260] [a] d ²⁸ = -9.86 ° (concentration: 1.014, CHCb).

[2261] MS 431 (M ⁺ ) [2262] Melting point 210.5-212.0 ° C.

Example 152

Preparation of 4-chlorobenzyl (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethoxy) phenyl] piperazine-1-carboxylate [2263] ( R) tert-butyl -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperazine-1-carboxylate prepared in Example 148 (300 mg, 0.65 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and then methylene chloride (2 ml) and triethylamine (2 ml) added. After stirring at room temperature for 5 minutes, the solution was concentrated under reduced pressure, and the residue was dissolved in DMF (15 ml). A mixture of 4-chlorobenzyl alcohol (186 mg, 1.31 mmol), 1,1'-carbonyldiimidazole (212 mg, 1.31 mmol) in DMF (5 ml) stirred at room temperature for 3 hours was added to the solution, followed by stirring at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving (R) -4- [4- (2-methyl- 4-chlorobenzyl 6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethoxy) phenyl] piperazine-1-carboxylate (313 mg,

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583/854 yield 91%) as a light yellow powder.

[2264] [oc] d ²⁸ = -10.84 ° (concentration: 1.006, CHCb) [2265] MS 527 (M ⁺ ) [2266] Melting point 184.5-187.5 ° C.

[2267] Using corresponding starting materials gave the compound of Example 153 in the same way as in Example 152.

Example 153 (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperazine-1-5-chlorobenzofuran-2- ilmethyl [2268] yield of 79%, melting point 195-197 ° C.

[2269] Using (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] piperidine-1-carboxylate ter-butyl prepared in Example 143, (R) -4- [4 (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] -1,2,3,6tetrahydropyridine-1 tert-butyl carboxylate prepared in Example 144, (R) -4- [4- (2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) benzoyl] piperazine-1carboxylate tert-butyl prepared in Example 145, or (R) -4- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperazine-1- ter-butyl carboxylate prepared in Example 147 gave the compounds of Examples 154 to 158 in the same manner as in Example 152.

Example 154 (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperidine-1 carboxylate 4-trifluoromethoxybenzyl [2270 ] 54% yield, melting point 202.5-204 ° C.

Example 155 (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] -1,2,3,6tetrahydropyridine-1 4-trifluoromethoxybenzyl carboxylate [2271] yield 67%, melting point 174.3-174.8 ° C.

Example 156 (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) benzoyl] piperazino1-carboxylate 4-trifluoromethoxybenzyl

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584/854 [2272] 86% yield, melting point 168.5-172 ° C.

Example 157 (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) benzoyl] piperazine-1-carboxylate ethyl [2273] yield of 85%, melting point 132-135 ° C.

Example 158 (R) -4- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperazine-1-4-trifluoromethoxybenzyl [2274] 50% yield, melting point 136.5-138 ° C.

Example 159

Preparation of (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxybenzyl) piperazin-1 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole [2275 ] (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] terp-butyl piperazine-1-carboxylate prepared in Example 148 (4.22 g,

9.60 mmol) was dissolved in methylene chloride (10 ml). Trifluoroacetic acid (30 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and methylene chloride (10 ml) and triethylamine (10 ml) were added. The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in dichloroethane. To the solution, 4-trifluoromethoxybenzaldehyde (1.64 ml, 11.5 mmol) and sodium triacetoxyborohydride (3.05 g, 14.4 mmol) were added with cooling in an ice bath, followed by stirring at room temperature for one day. To the other. To the reaction mixture, a saturated solution of sodium hydrogen carbonate and methylene chloride was added, and the solution was stirred and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and then crystallized from methylene chloride-ethyl acetate giving (R) -2-methyl-6-nitro-2 - {4- [4- (4-trifluoromethoxybenzyl) piperazin-1-yl] phenoxymethyl} 2,3-dihydroimidazo [2,1-b] oxazole (3.23 g, 63% yield) as a yellow powder

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585/854 clear.

[2276] Optical purity> 99.5% e.e.

[2277] [a] d ²⁸ = -8.25 ° (concentration: 1.018, CHCb) [2278] MS 533 (M ⁺ ) [2279] Melting point 213.5-217 ° C.

[2280] The compound of Example 159 was also prepared with Examples 160.

Example 160

Preparation of (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxybenzyl) piperazin-1 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole [2281 ] 4- [4- (4-trifluoromethoxybenzyl) piperazin-1-yl] phenol (3.36 g, 9.54 mmol) was dissolved in DMF (20 ml). Sodium hydride (420 mg, 10.5 mmol) was added to the solution at room temperature, and the solution was stirred for 15 minutes at 80 ° C. To the reaction mixture, (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (2.18 g, 10.0 mmol) was added with cooling in a bath ice, followed by stirring for another 15 minutes at 80 ° C. Ice water was added to the reaction mixture, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and then crystallized from methylene chloride ethyl acetate giving (R) -2-methyl-6-nitro-2- { 4- [4- (4-trifluoromethoxybenzyl) piperazin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole (2.0 g, 40% yield) as a light yellow powder.

[2282] Using (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] terp-butyl piperidine-1-carboxylate prepared in Example 143, (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] -1,2,3 was obtained, Tert-butyl 6-tetrahydropyridine-1-carboxylate prepared in Example 144, or (R) -4- [4- (2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) benzoyl ] ter-butyl piperazine-1-carboxylate prepared in Example 145 gave compounds of Examples

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586/854

161-163 in the same way as in Example 159.

Example 161 (R) -2-methyl-6-nitro-2- {4- [1- (4-trifluoromethoxybenzyl) pipendin-4-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole [2283] 45% yield, melting point 186-188 ° C.

Example 162 (R) -2-methyl-6-nitro-2- {4- [1- (4-trifluoromethoxybenzyl) -1,2,3,6-tetrahydropyridin-4yl] phenoxymethyl} -2,3-dihydroimidazo [2 , 1-b] oxazole [2284] 61% yield, melting point 168-174 ° C.

Example 163 (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) benzoyl] -1- (4trifluoromethoxybenzyl) piperazine [2285] 83% yield, melting point 155-156 ° C.

Example 164

Preparation of (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperazine-1-carboxylic acid 4-trifluoromethoxybenzylamide [2286 ] (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] terp-butyl piperazine-1-carboxylate prepared in Example 148 (120 mg, 0.26 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, then methylene chloride (2 ml) and triethylamine (2 ml) were added. The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in DMF (10 ml). A mixture of 4-trifluoromethoxybenzylamine (125 mg, 0.65 mmol) and 1,1'-carbonyldiimidazole (110 mg, 0.68 mmol) in DMF (5 ml) was added to the solution while stirring at room temperature for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was

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587/854 purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving (R) -4- [4- (4) trifluoromethoxybenzylamide acid] (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethoxy) phenyl] piperazine-1-carboxylic (48 mg, 32% yield) as a white powder.

[2287] MS 558 (M-18) ⁺ [2288] Melting point 166.5-168.5 ° C.

Example 165

Preparation of (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxybenzoyl) piperazin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole [2289] (R) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethoxy) phenyl] terp-butyl-piperazine-1-carboxylate prepared in Example 148 ( 300 mg, 0.65 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added with methylene chloride (10 ml), thethylamine (2 ml) and 4-thfluoromethoxybenzoyl chloride (0.15 ml, 0.98 mmol). The reaction mixture was stirred at room temperature for 1 hour, then poured into water, and extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and crystallized from methylene chloride-diisopropyl ether giving (R) -2-methyl-6-nitro- 2- {4- [4- (4-trifluoromethoxybenzoyl) piperazin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole (263 mg, 74% yield) as a white powder.

[2290] MS 547 (M ⁺ ) [2291] Melting point 201.5-203.2 ° C.

Example 166

Preparation of (R) -2-methyl-6-nitro-2- [4- (1-oxothiomorfolin-4-yl) phenoxymethyl] -2,3dihydroimidazo [2,1-b] oxazole

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588/854 [2292] (R) -2-methyl-6-nitro-2- [4- (thiomorpholin-4-yl) phenoxymethyl] -2,3-dihydroimidazo [2,1 b] oxazole prepared in Example 137 ( 85 mg, 0.23 mmol) was dissolved in methylene chloride (5 ml). M-chloroperbenzoic acid (59 mg, 0.24 mmol) was added to the solution, followed by stirring at room temperature for 20 minutes. The reaction mixture was diluted with methylene chloride. The solution was washed with a sodium thiosulfate solution, a saturated sodium hydrogen carbonate solution and a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was crystallized from methylene chloride-isopropyl ether giving (R) -2-methyl-6-nitro-2- [4- (1-oxothiomorfolin4-yl) phenoxymethyl] -2,3-dihydroimidazo [2,1- b] oxazole (59 mg, 67% yield) as a white powder.

[2293] MS 392 (M ⁺ ) [2294] Melting point 198-200 ° C.

Example 167

Preparation of N-methyl-N- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2 (4-trifluoromethoxyphenoxy) ethylamine [2295] A mixture of 2 -chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (84 mg, 0.39 mmol), N-methyl-2- (4trifluoromethoxyphenoxy) ethylamine (100 mg, 0.43 mmol ) and DMF (1 ml) was stirred at 6570 ° C for 8 hours. The reaction mixture was allowed to return to room temperature, poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving a yellow oil.

[2296] The yellow oil was dissolved in DMF (1 ml). Sodium hydride (11 mg, 0.28 mmol) was added to the solution, followed by stirring at room temperature for 1 hour. Ice water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and filtered. The resulting filtrate was

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589/854 concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and crystallized from methylene chloride-diisopropyl ether giving N-methyl-N- (2-methyl-6 -nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2- (4-trifluoromethoxyphenoxy) ethylamine (34 mg, 21% yield) as a white powder.

[2297] Melting point 86.4-89.2 ° C.

Example 168

Preparation of N-methyl-N- {2- [N-methyl- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) amino] ethyl} ter-butyl carbamate [2298] A mixture of 2-chloro-4-nitro-1 H-imidazole (5.97 g, 27.43 mmol), N-methyl {2- [N-methyl- (2-methyloxyran-2-ylmethyl) amino] ethyl} ter-butyl carbamate (10.53 g, 40.76 mmol), triethylamine (0.76 ml, 5.49 mmol) and 1-propanol (60 ml) was stirred at reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride. The organic phase was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving a yellow oil.

[2299] The yellow oil was dissolved in 1,4-dioxane (200 ml). Sodium hydride (500 mg, 12.5 mmol) was added to the solution, followed by stirring at reflux overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Ice water was added to the residue, and the solution was extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving N-methyl-N- {2- [Nmethyl- (2-methyl-6-nitro-2,3 -dihydroimidazo [2,1-b] oxazol-2-ylmethyl) amino] ethyl} ter-butyl carbamate (1.94 g, 13% yield) as a white powder.

[2300] ¹ H NMR (CDCb) δ ppm:

[2301] 1.45 (9H, s), 1.58 (3H, s), 2.38 (3H, s), 2.57 - 2.69 (3H, m), 2.79 (3H, s ),

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590/854

2.89 (1H, d, J = 14.9 Hz), 3.15 - 3.25 (2H, bm), 3.85 (1H, d, J = 14.9 Hz), 4.33 (1H , br), 7.52 (1H, s).

Example 169

Preparation of (S) -N-methyl-N- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 2- {4- [4- (trifluoromethyl) phenyl] piperazin-1-yl} ethylamine [2302] (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (523 mg, 2.41 mmol) and N -methyl-2- [4- (4-trifluoromethylphenyl) piperazin-1yl] ethylamine (900 mg, 3.13 mmol) was added to DMF (15 ml), followed by stirring at 70-80 ° C for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving a yellow oil.

[2303] The yellow oil was dissolved in DMF (15 ml). Sodium hydride (115 mg, 2.89 mmol) was added to the solution, followed by stirring at room temperature for 1 hour. Ice water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and crystallized from methylene chloride-diisopropyl ether giving (S) -N-methyl-N- (2 -methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2- {4- [4- (trifluoromethyl) phenyl] piperazin-1-yl} ethylamine (173 mg, yield 15%) as a white powder.

[2304] MS 468 (M ⁺ ) [2305] Melting point 148.0-150.5 ° C.

[2306] Using corresponding starting materials, compounds of Examples 170 to 177 were obtained in the same manner as in Example 169.

Example 170 (S) -N-methyl-N- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2- (4Petition 870190039560, from 26/04 / 2019, page 599/876

591/854 trifluoromethylphenoxy) ethylamine [2307] White powder, 12% yield [2308] MS 399 (MH) ⁺ [2309] Melting point 123.0-126.0 ° C.

Example 171 (S) -N-methyl-N- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2- (4trifluoromethoxyphenoxy) ethylamine [2310] Powder white, 45% yield [2311] MS416 (M ⁺ ) [2312] Melting point 112.5-115.0 ° C.

Example 172 (S) -N, N'-dimethyl-N- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -N '- (4trifluoromethylphenyl) - 1,2-ethylenediamine [2313] White powder, 24% yield [2314] MS413 (M ⁺ ) [2315] Melting point 135.5-137.5 ° C.

Example 173 (S) -4- [2- (N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethylamino) ethyl] piperazine-1-carboxylate ter butyl [2316] White powder, 30% yield [2317] MS 425 (M + H) ⁺ [2318] Melting point 149.5-151.8 ° C.

Example 174 (S) -N-Benzyl-N- [2- (4-trifluoromethoxyphenoxy) ethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethylamine [2319] Powder white, 25% yield [2320] Melting point 96.5-97 ° C.

Example 175 (S) -N-methyl-N- [3- (4-trifluoromethoxyphenoxy) propyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethylamine

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592/854 [2321] White powder, 50% yield [2322] Melting point 92-95 ° C.

Example 176 (S) -N-methyl-N- [2- (4-chlorophenoxy) ethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethylamine [2323] Powder white, 27% yield [2324] Melting point 130.5-132 ° C.

Example 177 (S) -N-methyl-N- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2- [4- (4trifluoromethylphenoxy) pipendin- 1-yl] ethylamine [2325] Light brown powder, 26% yield [2326] ¹ H NMR (CDCb) δ ppm:

[2327] 1.58 (3H, s), 1.70 -1.85 (2H, m), 1.98 (2H, br), 2.37 (3H, s), 2.25 - 2.50 (4H,

m), 2.50 - 2.80 (5H, m), 2.90 (1H, d, J = 14.9 Hz), 3.85 (1H, d, J = 9.5 Hz), 4, 37 (1H, m), 4.52 (1H, d, J = 14.9 Hz), 7.42 (2H, d, J = 8.7 Hz), 7.52 (1H, s), 7, 53 (2H, d, J = 8.7 Hz).

Example 178

Preparation of N- (2-ethoxycarbonylphenyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethylamine [2328] A mixture of 2-chloro-4-nitro-1 H- imidazole (891 mg, 6.04 mmol), 1- (2methyloxyran-2-ylmethyl) -1H-benzo [d] [1,3] oxazin-2,4-dione (1.41 g, 6.04 mmol) , sodium acetate (545 mg, 6.64 mmol) and ethanol (10 ml) was stirred at reflux for 10 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride. The organic phase was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (20 ml). Sodium hydride (219 mg, 5.48 mmol) was added to the solution, followed by stirring at reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Ice water was added to the residue and the precipitates were removed

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593/854 by filtration, which were purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving N- (2-ethoxycarbonylphenyl) -2-methyl-6nitro-2,3 -dihydroimidazo [2,1-b] oxazol-2-ylmethylamine (1.15 g, 55% yield) as a white powder.

[2329] Melting point 162.5-163.2 ° C.

Example 179

Preparation of (S) -1 - [2-hydroxy-3- (N-methyl-benzylamino) -2-methylpropyl] -2-chloro-4-nitroimidazole [2330] A mixture of (R) -2-chloro-1- ( 2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (500 mg, 2.3 mmol), N-methylbenzylamine (334 mg, 2.76 mmol) and DMF (2.5 ml) was stirred at 60 ° C for 9 hours. The reaction mixture was allowed to return to room temperature and added with water, followed by extraction with ethyl acetate twice. The organic phases were combined, washed with water three times, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving (S) -1- [2-hydroxy-3- (Nmethyl-N-benzylamino) -2 -methylpropyl] -2-chloro-4-nitroimidazole (712 mg, 91% yield) as a yellow oil.

[2331] ¹ H NMR (CDCb) δ ppm:

[2332] 1.13 (3H, s), 2.37-2.57 (5H, m), 3.51 (1H, d, J = 12.9 Hz), 3.72 (1H, d, J =

12.9 Hz), 3.85 (2H, s), 7.16 - 7.39 (5H, m), 7.87 (1H, s).

[2333] Using corresponding starting materials, compounds of Examples 180 to 187 were obtained in the same manner as in Example 179.

Example 180 (S) -1- {2-hydroxy-3- [N-methyl- (3-chlorobenzyl)] amino-2-methyl} propyl-2-chloro-4-nitroimidazole [2334] 98% yield [2335 ] ¹ H NMR (CDCb) δ ppm:

[2336] 1.15 (3H, s), 2.35-2.57 (5H, m), 3.53 (1H, d, J = 13.3 Hz), 3.67 (1H, d, J =

13.3 Hz), 3.92 (2H, s), 7.10-7.31 (4H, m), 7.95 (1H, s).

Example 181

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594/854 (S) -1 - {2-hydroxy-3- (N-methyl-4-chlorobenzylamino) -2-methylpropyl] -2-chloro-4-nitroim idazole [2337] 86% yield [2338] ¹ H NMR (CDCb) δ ppm:

[2339] 1.13 (3H, s), 2.33-2.59 (5H, m), 3.53 (1H, d, J = 13.2 Hz), 3.68 (1H, d, J =

13.2 Hz), 3.92 (2H, s), 7.19 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.96 (1H , s). Example 182 (S) -1- [2-hydroxy-3- (N-methyl-4-trifluoromethoxybenzylamino) -2-methylpropyl] -2-chloro-4nitroimidazole [2340] 98% yield [2341] ¹ H NMR (CDCb ) δ ppm:

[2342] 1.13 (3H, s), 2.37 (3H, s), 2.47 (1H, d, J = 13.9 Hz), 2.58 (1H, d, J = 13.9

Hz), 3.58 (1H, d, J = 13.3 Hz), 3.72 (1H, d, J = 13.3 Hz), 3.94 (2H, s), 7.19 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.99 (1H, s).

Example 183 (S) -1- [2-hydroxy-3- (N-methyl-4-trifluoromethylbenzylamino) -2-methylpropyl] -2-chloro-4nitroimidazole [2343] 100% yield [2344] ¹ H NMR (CDCb ) δ ppm:

[2345] 1.15 (3H, s), 2.38 (3H, s), 2.50 (1H, d, J = 13.9 Hz), 2.60 (1H, d, J = 13.9

Hz), 3.65 (1H, d, J = 13.6 Hz), 3.79 (1H, d, J = 13.6 Hz), 3.97 (2H, s), 7.41 (2H, d, J =

8.2 Hz), 7.61 (2H, d, J = 8.2 Hz), 8.00 (1H, s).

Example 184 (S) -1- [2-hydroxy-3- (N-methyl-4-methoxybenzylamino) -2-methylpropyl] -2-chloro-4-nitroimidazole [2346] 85% yield [2347] ¹ H NMR (CDCb) δ ppm:

[2348] 1.12 (3H, s), 2.36-2.50 (5H, m), 3.45 (1H, d, J = 12.8 Hz), 3.64 (1H, d, J =

12.8 Hz), 3.80 (3H, s), 3.84 (2H, s), 6.84 (2H, dd, J = 1.9 Hz, 8.6 Hz), 7.13 (2H , dd, J = 1.9 Hz, 8.6 Hz), 7.89 (1H, s).

Example 185 (S) -1- [2-hydroxy-3- (N-methyl-4-dimethylaminobenzylamino) -2-methylpropyl] -2-chloro-4 Petition 870190039560, from 26/04/2019, p. 603/876

595/854 nitroimidazole [2349] 94% yield [2350] ¹ H NMR (CDCb) δ ppm:

[2351] 1.11 (3H, s), 2.34 - 2.47 (5H, m), 2.93 (s, 6H), 3.39 (1H, d, J = 12.8 Hz),

3.60 (1H, d, J = 12.8 Hz), 3.81 (2H, s), 6.65 (2H, d, J = 8.7 Hz), 7.03 (2H, d, J = 8.7 Hz), 7.87 (1H, s).

Example 186 (S) -1- [2-hydroxy-3- (N-methyl-phenylamino) -2-methylpropyl] -2-chloro-4-nitroimidazole [2352] 92% yield [2353] ¹ H NMR (CDCb ) δ ppm:

[2354] 1.24 (3H, s), 3.06 (3H, s), 3.40 (2H, s), 4.05 (1H, d, J = 14.2 Hz), 4.13 ( 1H, d, J = 14.2 Hz), 6.74-6.89 (3H, m), 7.17-7.34 (2H, m), 8.04 (1H, s).

Example 187 (S) -1- [2-hydroxy-3- (N-methyl-4-chlorophenylamino) -2-methylpropyl] -2-chloro-4-nitroimidazole [2355] 92% yield [2356] ¹ H NMR (CDCb) δ ppm:

[2357] 1.24 (3H, s), 3.04 (3H, s), 3.38 (2H, s), 4.08 (2H, s), 6.74 (2H, dd, J = 2 ,1

Hz, 7.2 Hz), 7.19 (2H, dd, J = 2.1 Hz, 7.2 Hz), 8.02 (1H, s).

Example 188

Preparation of (S) -2- (N-benzyl-N-methyl) aminomethyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2358] To a mixture of (S) -1 - [2-hydroxy-3- (N-methyl-benzylamino) -2-methylpropyl] -2chloro-4-nitroimidazole prepared in Example 179 (710 mg, 2.1 mmol) and DMF (2.1 ml), was added if sodium hydride (101 mg, 2.51 mmol), followed by stirring for 2 hours with cooling in an ice bath. To the reaction mixture, ethyl acetate (0.7 ml) and water (5 ml) were added in that order. The precipitates were removed by filtration and dissolved in isopropyl alcohol (10 ml) with stirring at reflux. Activated carbon (28 mg) was added to the solution, followed by stirring at reflux for 20 minutes. After filtration, isopropyl ether (3 ml) was added to the solution, and the mixture was allowed to rest. The precipitates were collected giving (S) -2- (N

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596/854 benzyl-N-methyl) aminomethyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (248 mg, 39% yield) as a yellow powder.

[2359] Melting point 132.5-133 ° C.

[2360] Using corresponding starting materials, compounds of Examples 189 to 196 were obtained in the same manner as in Example 188.

Example 189 (S) -2- [N- (4-chlorobenzyl) -N-methylamino] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole [2361] yield of 44%, melting point 129-129.5 ° C.

Example 190 (S) -2- [N- (3-chlorobenzyl) -N-methylamino] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole [2362] 65% yield, melting point 177.5-178.5 ° C.

Example 191 (S) -2- [N- (4-trifluoromethoxybenzyl) -N-methylamino] methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2363] yield of 53%, melting point 145-146 ° C.

Example 192 (S) -2- [N- (4-trifluoromethylbenzyl) -N-methylamino] methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2364] 49% yield, melting point 130-132 ° C.

Example 193 (S) -2- [N- (4-methoxybenzyl) -N-methylamino] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole [2365] 59% yield, melting point 144-147 ° C.

Example 194 (S) -2- [N- (4-dimethylaminobenzyl) -N-methylamino] methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2366] yield of 47%, melting point 168-169 ° C.

Example 195

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597/854 (S) -2- (N-Phenyl-N-methylamino) methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2367] 55% yield, point melting temperature 147-148 ° C.

Example 196 (S) -2- [N- (4-chlorophenyl) -N-methylamino] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole [2368] 34% yield, melting point 174-175 ° C.

Example 197

Preparation of 4- (S) -4- [2- (N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethylamino) ethyl] piperazine-1-carboxylate trifluoromethylbenzyl [2369] (S) -4- [2- (N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethylamino) ethyl] piperazine-1-carboxylate tert-butyl prepared in Example 173 (300 mg, 0.71 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and received the addition of methylene chloride (2 ml) and triethylamine (2 ml). After stirring for 5 minutes at room temperature, the solution was concentrated under reduced pressure. The residue was dissolved in DMF (15 ml). A mixture of 4trifluoromethylbenzyl alcohol (373 mg, 2.12 mmol) and 1,1'-carbonyldiimidazole (344 mg, 2.12 mmol) in DMF (5 ml) stirred at room temperature for 3 hours was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over magnesium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) and crystallized from methylene chloride-isopropyl ether giving 4-trifluoromethylbenzyl (S) 4- [2- (N- methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethylamino) ethyl] piperazine-1-carboxylate (196 mg, 53% yield) as a white powder.

[2370] MS 509 (MH ₂ O) ⁺ [2371] Melting point 77.2-76.9 ° C.

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Example 198

Preparation of (S) -N-methyl-N- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 2- [4- (4-trifluoromethylbenzyl) piperazin -1-yl] ethylamine [2372] (S) -4- [2- (N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethylamino) ethyl] piperazine Tert-butyl -1-carboxylate prepared in Example 173 (400 mg, 0.94 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and received the addition of methylene chloride (2 ml) and triethylamine (2 ml). After stirring for 5 minutes at room temperature, the solution was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). To the solution, 4- (trifluoromethyl) benzaldehyde (0.4 ml, 2.83 mmol), sodium cyanotrihydroborate (178 mg, 2.83 mmol) and acetic acid (0.2 ml) were added, followed by stirring at temperature room for 30 minutes. A saturated solution of sodium hydrogen carbonate and methylene chloride was added to the solution, followed by stirring, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving (S) -N-methyl-N- (2-methyl -6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2- [4- (4-trifluoromethylbenzyl) piperazin-1-yl] ethylamine (307 mg, 68% yield) as a White powder.

[2373] MS 482 (M ⁺ ) [2374] Melting point 102.0-104.5 ° C.

Example 199

Preparation of ethyl (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate [2375] 2,4-Dinitro-1 H-imidazole (0.688 g, 3.92 mmol) and phenyl oxiran-2-ylmethylcarbamate (1.04 g, 5.87 mmol) were dissolved in ethanol (20 ml). Sodium acetate (0.386 g, 4.70 mmol) was added to the solution, followed by stirring at reflux overnight. To the reaction mixture, a saturated solution of sodium hydrogen carbonate and methylene chloride was added, and the solution was extracted with

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599/854 methylene chloride. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) and treated with diisopropyl ether giving (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) ethyl carbamate (0.116 g, 11.6% yield) as a light brown solid.

[2376] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[2377] 1.15 (3H, t, J = 7.1 Hz), 3.41 -3.51 (2H, m), 3.93-4.11 (3H, m), 4.38 (1H , dd, J = 8.6 Hz, 10.7 Hz), 5.31 -5.47 (1H, m), 7.52 (1H, br), 8.13 (1H, s).

Example 200

Preparation of benzyl (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate [2378] 2,4-Dinitro-1 H-imidazole (3 g, 19 mmol) and benzyl (2-methyloxyran-2ylmethyl) carbamate (4.31 g, 19 mmol) were dissolved in ethanol (20 ml). Sodium acetate (1.56 g, 19.0 mmol) was added to the solution, followed by stirring at 70 ° C overnight. To the reaction mixture, a saturated solution of sodium hydrogen carbonate and methylene chloride, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1, methylene chloride / methanol = 50/1) and recrystallized from ethyl acetate-methylene chloride giving ( Benzyl 2-methyl-6-nitro2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate (0.298 g, 4.7% yield) as a colorless solid.

[2379] Melting point 171.3-172.2 ° C [2380] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[2381] 1.55 (3H, s), 3.46 (2H, d, J = 6.3 Hz), 4.06 (1H, d, J = 11.0 Hz), 4.25 (1H, d,

J = 11.0 Hz), 5.03 (2H, s), 7.19 - 7.41 (5H, m), 7.76 (1H, t, J = 6.3 Hz), 8.13 ( 1H, s). Example 201

Preparation of 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methylmethyl trifluoroacetate

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600/854 [2382] A mixture of benzyl (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) carbamate prepared in Example 200 (190 mg, 0.57 mmol) , trifluoroacetic acid (4 ml) and methylene chloride (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was treated with diethyl ether giving 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethylamine trifluoroacetate (120 mg, 67% yield) as a light yellow powder .

[2383] ¹ H NMR (DMSO-de) δ ppm:

[2384] 1.35 (3H, s), 3.23 (1H, d, J = 9.6 Hz), 3.49 (1H, d, J = 9.6 Hz), 3.82 - 3, 98 (2H, m), 7.98 (1H, s), 12.22 (1H, s).

[2385] Using corresponding starting materials, compounds of Examples 202 to 204 were obtained in the same manner as in Example 200.

Example 202 Benzyl N-methyl- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate [2386] 14% yield, melting point 150.3 -151.6 ° C.

Example 203 Benzyl (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate [2387] 11% yield [2388] ¹ H NMR (DMSO-de) δ ppm:

[2389] 3.45 - 3.59 (2H, m), 4.07 (1H, dd, J = 6.6 Hz, 10.8 Hz), 4.39 (1H, dd, J = 8.6

Hz, 10.8 Hz), 5.04 (2H, s), 5.32 - 5.50 (1H, m), 7.23-7.41 (5H, m), 7.71 (1H, br ), 8.13 (1H, s).

Example 204 (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) ter-butyl carbamate [2390] 27% yield [2391] ¹ H NMR (CDCb) δ ppm:

[2392] 1.43 (9H, s), 3.65 (2H, dd, J = 4.3 Hz, 6.2 Hz), 4.20 (1H, dd, 7.0 Hz, 10.5

Hz), 4.36 (1H, dd, J = 8.6 Hz, 10.5 Hz), 5.20 (1H, t, J = 6.2 Hz), 5.35 - 5.48 (1H, m), 7.56 (1H, s).

Example 205

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Preparation of 4-chlorobenzyl (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate [2393] 2,4-Dinitro-1 H-imidazole (0.518 g , 3.28 mmol) and 4-chlorobenzyl (2-methyloxyran-2-ylmethyl) carbamate (2.097 g, 8.20 mmol) and sodium acetate (0.538 g, 6.56 mmol) in ethanol (6 ml) were stirred at reflux for 1 hour. Water was added to the solution and the precipitates were removed by filtration. The resulting solid was treated with diethyl ether giving 4-chlorobenzyl (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) carbamate (0.197 g, 16% yield) as a colorless solid.

[2394] Melting point 221.0-221.8 ° C.

[2395] Using N-methyl- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) benzyl carbamate prepared in Example 202 gave the compound of Example 206 in the same way as in Example 201.

Example 206

N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methylmethylamine trifluoroacetate [2396] Melting point 176.2-178.8 ° C.

[2397] Using corresponding starting materials, compounds of Examples 207 to 211 were obtained in the same manner as in Example 205.

Example 207 4-Fluorobenzyl carbamate (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) [2398] 25% yield, melting point 200.4-202 , 1 ° C.

Example 208 Ethyl (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate [2399] yield 26%, melting point 182.5-183.4 ° C.

Example 209 (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 4-trifluoromethoxybenzyl carbamate [2400] 17% yield, melting point 182.3-184.4 ° C.

Example 210

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602/854 (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 4-chlorobenzyl carbamate [2401] 17% yield, melting point 182.6-182.9 ° Ç.

Example 211 4-fluorobenzyl (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate [2402] 17% yield, melting point 164.6-165.1 ° C .

Example 212

Preparation of 4-fluorobenzyl [3- (2-chloro-4-nitroim-idazol-1-yl) -2-hydroxy-2-methyl] [2403] 2-chloro-4-nitro-1 H- imidazole (0.953 g, 6.46 mmol) and 4-fluorobenzyl N-methyl- (2-methyloxyran-2ylmethyl) carbamate (1.964 g, 7.75 mmol) were dissolved in ethanol (20 ml). Sodium acetate (0.583 g, 7.11 mmol) was added to the solution, followed by stirring at reflux overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the solution was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy -2-methylpropyl] -N-methylcarbamate of 4-fluorobenzyl (1.683 g, 65% yield) as a colorless oil.

[2404] ¹ H NMR (CDCb) δ ppm:

[2405] 1.17 (3H, s), 3.06 (3H, s), 3.25 (1H, d, J = 14.7 Hz), 3.51 (1H, d, J = 14.7

Hz), 4.00 (2H, s), 5.12 (2H, s), 6.95 - 7.09 (2H, m), 7.27 - 7.41 (2H, m), 8.07 (1H, s).

[2406] Using 4-fluorobenzyl N-methyl- (oxiran-2-ylmethyl) carbamate gave the compound of Example 213 in the same manner as in Example 212.

Example 213 4-fluorobenzyl [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxypropyl] -N-methylcarbamate [2407] 51% yield [2408] ¹ H NMR (CDCb) δ ppm:

[2409] 3.04 (3H, s), 3.27 - 3.55 (2H, m), 3.73 - 4.23 (4H, m), 5.11 (2H, s), 7.00 7.14 (2H, m), 7.27 - 7.41 (2H, m), 7.96 (1H, s).

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Example 214

Preparation of 4-fluorobenzyl N-methyl- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) [2410] [3- (2-chloro-4-nitroimidazole -1-yl) -2-hydroxy-2-methylpropyl] -N-methylcarbamate of 4-fluorobenzyl prepared in Example 212 (1.683 g, 4.20 mmol) was dissolved in 1,4-dioxane (30 ml). Sodium hydride (0.185 g, 4.62 mmol) was added to the solution, followed by stirring at room temperature for 1 hour and then stirring at reflux for 7 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the precipitates were removed by filtration and purified by column chromatography on silica gel (n-hexane / acetone = 2/1). The resulting solid was treated with a mixture of n-hexane and ethyl acetate giving N-methyl- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) carbamate 4-fluorobenzyl (0.381 g, 25% yield) as a colorless solid.

[2411] Melting point 168.9-169.9 ° C.

[2412] Using 4-fluorobenzyl [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxypropyl] -Nomethylcarbamate prepared in Example 213 gave the compound of Example 215 in the same manner as in Example 214.

Example 215 N-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethylcarbamate of 4-fluorobenzyl [2413] 16% yield, melting point 124.5-128.1 ° Ç.

[2414] Using corresponding starting materials, compounds of Examples 216 to 220 were obtained in the same manner as in Example 179.

Example 216 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3 - {[1 - (4-chlorophenyl) piperidin-4-yl] -N-methylamino} -2hydroxy-2-methylpropane [2415] yellow solid, 98% yield [2416] ¹ H NMR (CDCb) δ ppm:

[2417] 1.13 (3H, s), 1.57 - 1.82 (4H, m), 2.38 - 2.71 (4H, m), 2.40 (3H, m), 3.65 3.71 (2H, m), 3.82 (1H, s), 3.89 - 4.01 (2H, m), 6.81 - 6.86 (2H, m), 7.16 - 7, 22 (2H, m), 8.06 (1H, s).

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Example 217 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3 - {[1 - (4-trifluoromethoxyphenyl) piperid in-4-yl] -Nomethylamino} -2-hydroxy -2-methylpropane [2418] yellow solid, 91% yield [2419] ¹ H NMR (CDCb) δ ppm:

[2420] 1.13 (3H, s), 1.59 - 1.83 (4H, m), 2.41 (3H, s), 2.43 - 2.73 (5H, m), 3.66 3.73 (2H, m), 3.84 (1H, s), 3.93 (1H, d, J = 14.2 Hz), 4.00 (1H, d, J = 14.2 Hz), 6.86 6.91 (2H, m), 7.07 - 7.12 (2H, m), 8.06 (1H, s).

Example 218 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3 - {[1 - (4-trifluorom ethylphenyl) piperid in-4-yl] -Nomethylamino} -2-hydroxy -2-methylpropane [2421] yellow solid, 96% yield [2422] ¹ H NMR (CDCb) δ ppm:

[2423] 1.13 (3H, s), 1.54 - 1.70 (2H, m), 1.77 - 1.84 (2H, m), 2.40 (3H, s), 2.42 -

2.60 (3H, m), 2.72 - 2.82 (2H, m), 3.79 (1H, s), 3.84 - 3.89 (2H, m), 3.92 (1H, d, J = 14.2 Hz), 3.99 (1H, d, J = 14.2 Hz), 6.91 (2H, d, J = 8.7 Hz), 7.46 (2H, d, J = 8.7 Hz), 8.06 (1H, s).

Example 219 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3 - {[1 - (4-cyanophenyl) piperidin-4-yl] -N-methylamino} -2hydroxy-2-methylpropane [2424] yellow solid, 89% yield [2425] ¹ H NMR (CDCb) δ ppm:

[2426] 1.13 (3H, s), 1.51 - 1.65 (2H, m), 1.77 - 1.84 (2H, m), 2.39 (3H, s), 2.42 2.62 (3H, m), 2.76 - 2.88 (2H, m), 3.75 (1H, s), 3.88 - 4.03 (4H, m), 6.81 - 6, 88 (2H, m), 7.45 - 7.53 (2H, m), 8.05 (1H, s).

Example 220 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3 - {[1 - (tert-butoxycarbonyl) piperidin-4-yl] -Nmethylamino} -2-hydroxy-2-methylpropane [2427] yellow solid [2428] ¹ H NMR (CDCb) δ ppm:

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605/854 [2429] 1.11 (3H, s), 1.46 (9H, s), 1.50-1.80 (4H, m), 2.37 (3H, s), 2.40 - 2.75 (5H,

m), 3.90 (1H, d, J = 14.2 Hz), 3.99 (1H, d, J = 14.2 Hz), 4.22 (2H, br), 8.05 (1H, s). [2430] Using compounds prepared in Examples 216 to 220, the compounds of Examples 221 to 225 were obtained in the same manner as in Example 188. Example 221 (S) -2 - {[1- (4-chlorophenyl) piperidin- 4-yl] -N-methylaminomethyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2431] White powder, 47% yield [2432] MS 406 (M + 1) ⁺ [2433] Melting point 179.2-182.1 ° C.

Example 222 (S) -2 - {[1- (4-trifluoromethoxyphenyl) pipendin-4-yl] -N-methylaminomethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2434 ] Melting point 127.2-129.7 ° C.

Example 223 (S) -2 - {[1- (4-trifluoromethylphenyl) pipendin-4-yl] -N-methylaminomethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2435 ] Melting point 131.5-133.6 ° C.

Example 224 (S) -2 - {[1- (4-cyanophenyl) piperidin-4-yl] -N-methylaminomethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2436 ] Melting point 149-152 ° C.

Example 225 (S) -2 - {[1- (Ter-butoxycarbonyl) piperidin-4-yl] -N-methylaminomethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2437 ] Light yellow powder, 37% yield [2438] Melting point 138.5-140.3 ° C.

Example 226

Preparation of (S) -2 - {[1- (4-trifluoromethylbenzyloxycarbonyl) piperidin-4-yl] -Nmethylaminomethyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole

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606/854 [2439] (S) -2 - {[1 - (Ter-butoxycarbonyl) piperidin-4-yl] -N-methylaminomethyl} -2-methyl-6nitro-2,3-dihydroimidazo [2,1-b ] oxazole prepared in Example 225 (400 mg, 1.01 mmol) was dissolved in methylene chloride (1 ml). Trifluoroacetic acid (1 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and received the addition of methylene chloride (1 ml) and triethylamine (2 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure, and the residue was dissolved in DMF (8 ml). A mixture of alcohol 4 (trifluoromethyl) benzyl (267 mg, 1.51 mmol) and 1,1'-carbonyldiimidazole (246 mg, 1.51 mmol) in DMF (2 ml) stirred at room temperature was added to the solution 4 hours, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving (S) -2 - {[1- (4trifluoromethylbenzyloxycarbonyl) pipendin -4-yl] -N-methylaminomethyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (341 mg, 68% yield) as a light yellow powder. [2440] Melting point 110.6-113.1 ° C.

[2441] Using corresponding starting materials, compounds of Examples 227 and 228 were obtained in the same manner as in Example 226.

Example 227 (S) -2 - {[1- (4-trifluoromethoxybenzyloxycarbonyl) pipendin-4-yl] -N-methylaminomethyl} -2-methyl6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2442 ] Melting point 84.2-86.8 ° C.

Example 228 (S) -2 - {[1- (4-chlorobenzyloxycarbonyl) piperidin-4-yl] -N-methylaminomethyl} -2-methyl-6-nitro2,3-dihydroimidazo [2,1-b] oxazole [2443 ] Melting point 116.2-116.6 ° C.

Example 229

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Preparation of 2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzyloxy) piperidin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole [2444] 2-chloro-1- (2- methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (122 mg, 0.56 mmol) and 4- [4- (trifluoromethyl) benzyloxy] piperidine (188 mg, 4.86 mol) were dissolved in DMF (10 ml), followed by stirring at 70-75 ° C for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving a yellow oil. [2445] The yellow oil was dissolved in DMF (10 ml). Sodium hydride (134 mg, 3.36 mmol) was added to the solution with cooling in an ice bath, and the solution was stirred at room temperature for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and crystallized from ethyl acetate-diisopropyl ether giving 2-methyl-6-nitro-2- [4 - (4trifluoromethylbenzyloxy) piperidin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole (41 mg, 17% yield) as a white powder.

[2446] MS 440 (M-1) ⁺ [2447] ¹ H NMR (CDCb) δ ppm:

[2448] 1.45 - 1.70 (2H, m), 1.60 (3H, s), 1.75 - 1.88 (2H, m), 2.26 - 2.40 (1H, m) ,

2.45 - 2.55 (2H, m), 2.72 - 2.95 (3H, m), 3.38 (1H, m), 3.89 (1H, d, J = 9.6 Hz) , 4.31 (1H, d, J = 9.6 Hz), 4.54 (2H, s), 7.43 (2H, d, J = 8.2 Hz), 7.53 (1H, s) , 7.79 (2H, d, J = 8.2 Hz).

Example 230

Preparation of 1- (2-chloro-4-nitroim idazol-1-yl) -2-methyl-3- [4- (4trifluoromethylphenoxy) piperidin-1-yl] propan-2-ol [2449] To a solution of 2 -chloro-1- [2-hydroxy-2-methyl-3- (4

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608/854 methylbenzenesulfonyloxy) propyl] -4-nitroimidazole prepared in Example 5 (0.30 g, 0.77 mmol) and 4- (4-trifluoromethylphenoxy) pipendin (0.21 g, 0.85 mmol) in DMF (6 ml), sodium iodide (0.13 g, 0.77 mmol) and triethylamine (0.12 ml, 0.77 mmol) were added, followed by stirring at 80 ° C for 7 hours. To the reaction mixture, water was added, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 1- (2-chloro-4-nitroimidazole-1-yl) -2-methyl-3- [4- (4trifluoromethylphenoxy) piperidin-1-yl] propan-2-ol (0.23 g, 63% yield) as a yellow oil.

[2450] ¹ H NMR (CDCb) δ ppm:

[2451] 1.14 (3H, s), 1.76 - 2.04 (4H, m), 2.36 (1H, d, J = 14.0 Hz), 2.43 - 2.72 (3H ,

m), 2.76 - 3.00 (2H, m), 3.46 - 3.52 (1H, br), 3.98 (2H, s), 4.37 - 4.50 (1H, m) , 6.91 7.00 (2H, m), 7.48 - 7.61 (2H, m), 8.05 (1H, s).

[2452] Using corresponding starting materials, the compound of Example 231 was obtained in the same way as in Example 230.

Example 231

- (2-chloro-4-nitroim idazol-1-yl) -2-methyl-3- [4- (4-trifluoromethoxyphenoxy) piperidin-1 yl] propan-2-ol [2453] 61% yield [2454] ¹ H NMR (CDCb) δ ppm:

[2455] 1.14 (3H, s), 1.74-2.04 (4H, m), 2.35 (1H, d, J = 13.9 Hz), 2.40 (1H, d, J =

13.9 Hz), 2.43 - 2.70 (2H, m), 2.74 - 3.00 (2H, m), 3.98 (2H, s), 4.25 - 4.41 (1H , m), 6.86-6.92 (2H, m), 7.11 -7.15 (2H, m), 8.05 (1H, s).

Example 232

Preparation of 1- (2-chloro-4-nitroim idazol-1-yl) -2-methyl-3- [4- (4trifluoromethoxyphenylamino) piperidin-1-yl] propan-2-ol [2456] A solution of 2- chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (0.3 g, 1.38 mmol) and N- (piperidin-4-yl) -4-fluoromethoxyaniline (0, 43 g, 1.66 mmol) in DMF (8 ml) was stirred at 80 ° C for 2 hours. To the mixture of

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609/854 reaction, water was added, and the solution was extracted with ethyl acetate, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving 1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethoxyphenylamino) piperidin-1-yl] propan-2-ol (0.37 g, 56% yield) as a yellow oil.

[2457] ¹ H NMR (CDCb) δ ppm:

[2458] 1.13 (3H, s), 1.39 - 1.63 (2H, m), 1.96-2.09 (2H, m), 2.47 (1H, d, J = 13, 9

Hz), 2.43 - 2.63 (3H, m), 2.67 - 2.83 (1H, m), 2.87 - 3.02 (1H, m), 3.15 - 3.39 ( 1H, m), 3.41 - 3.72 (2H, m), 3.97 (2H, s), 6.46 - 6.59 (2H, m), 6.96 - 7.09 (2H, m), 8.05 (1H, s). Example 233

Preparation of 2-methyl-6-nitro-2- [4- (4-trifluoromethylphenoxy) piperidin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole [2459] To a solution of 1- (2- chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethylphenoxy) piperidin-1-yl] propan-2-ol prepared in Example 230 (225 mg, 0.49 mmol) in DMF ( 2.5 ml), sodium hydride (23 mg, 0.59 mmol) was added, followed by stirring for 1 hour with cooling in an ice bath. To the reaction mixture, ice water and ethyl acetate were added. The precipitates were removed by filtration, washed with water, recrystallized from methylene chloride-diisopropyl ether and then washed with n-hexane giving 2-methyl-6-nitro-2- [4- (4thfluoromethylphenoxy) pipehdin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole (80 mg, 39% yield) as a light yellow solid.

[2460] Melting point 113-114 ° C.

[2461] Using corresponding starting materials, the compound of Example 234 was obtained in the same way as in Example 233.

Example 234 2-methyl-6-nitro-2- [4- (4-thfluoromethoxyphenoxy) pipehdin-1-ylmethyl] -2,3-dihydroimidazo [2,1b] oxazole [2462] Melting point 117-119 ° C.

Example 235

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Preparation of 2- [4- (4-trifluoromethoxyphenyl) aminopipendin-1 -yl] methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2463] Using 1 - (2-chloro- 4-nitro-imidazol-1-yl) -2-methyl-3- [4- (4trifluoromethoxyphenylamino) piperidin-1-yl] propan-2-ol prepared in Example 233 (369 mg, 0.77 mmol) was obtained se2- [4- (4-trifluoromethoxyphenylamino) piperidin-1 -yl] methyl-2-methyl6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (25 mg, 7% yield) as a yellow powder in the same way as in Example 232.

[2464] MS 441 (M ⁺ ) [2465] ¹ H NMR (CDCb) δ ppm:

[2466] 1.11 - 1.40 (2H, m), 1.61 (3H, s), 1.85-2.01 (2H, m), 2.37 (1H, dt, J = 2, 7

Hz, 11.4 Hz), 2.46 - 2.59 (2H, m), 2.76 - 2.84 (1H, m), 2.87 (1H, d, J = 14.9 Hz), 2.95 -3.03 (1H, m), 3.10-3.25 (1H, m), 3.50 (1H, d, J = 7.8 Hz), 3.90 (1H, d, J = 9.7 Hz), 4.29 (1H, d, J = 9.7 Hz), 6.46 - 6.52 (2H, m), 6.98 - 7.01 (2H, m), 7.50 (1H, s). Example 236

Preparation of N-methyl- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] ter-butyl carbamate [2467] 2- chloro-4-nitro-1 H-imidazole (1.08 g, 7.31 mmol), tert-butyl N-methyl- [1 - (2-methyloxyran-2ylmethyl) piperidin-4-yl] carbamate (2, 08 g, 7.31 mmol) and sodium acetate (660 mg, 8.04 mmol) in 1-propanol (15 ml) were stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was added water, and the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1), crystallized from methylene chloride isopropyl ether giving N-methyl- [1- (2-methyl-6-nitro- 2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] tert-butyl carbamate (348 mg, 12% yield) as a white powder.

[2468] MS 396 (M + 1) ⁺ [2469] Melting point 198.8-201.1 ° C.

Example 237

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Preparation of benzyl N-methyl- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] carbamate [2470] N-methyl- {1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl} benzyl carbamate prepared in Example 236 (207 mg, 0.52 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride (5 ml), triethylamine (1 ml) and benzyl chlorocarbonate (0.15 ml, 1.05 mmol) were added to the residue, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from isopropyl ethyl acetate giving N-methyl- [1- (2-methyl-6-nitro- Benzyl 2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] carbamate (184 mg, 82% yield) as a white powder.

[2471] MS 430 (M + H) ⁺ [2472] Melting point 138.7-139.2 ° C.

[2473] Using 4-chlorobenzyl chlorocarbonate, the compound of Example 238 was obtained in the same manner as in Example 237. Also, using 4-chlorophenylacetyl chloride, the compound of Example 239 was obtained in the same manner as in Example 237 .

Example 238 N-methyl- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] 4-chlorobenzyl carbamate [2474] melting 147.2-149.2 ° C.

Example 239 2- {4- [N- (4-chlorophenylacetyl) -N-methyl] aminopiperidin-1-yl} methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2475] Melting point 206.8-208 ° C.

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Example 240

Preparation of 2-methyl-2- {4- [N-methyl-N- (4-trifluoromethoxyphenyl)] aminopiperidin-1 yl} methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2476 ] To a solution of 2- [4- (4-trifluoromethoxyphenyl) aminopiperidin-1-yl] methyl-2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 235 (60 mg, 0.14 mmol) in methanol (2 ml), a 37% formaldehyde solution (51 μΙ, 0.70 mmol) and sodium cyanothrihydroborate (26 mg, 0.42 mmol) were added, followed by stirring at temperature room for another 30 minutes. To the reaction mixture, acetic acid (23 μΙ, 0.42 mmol) was added, followed by stirring at room temperature for 1 hour with cooling in an ice bath. To the reaction mixture, a solution of sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 1/1) and crystallized from diisopropyl ether giving 2-methyl-2- {4- [N-methyl-N- (4-trifluoromethoxyphenyl)] aminopiperidin-1-yl} methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (40 mg, 65% yield) as a light yellow solid.

[2477] Melting point 135-136 ° C.

Example 241

Preparation of 2- [4- (4-chlorobenzyl) oxipiperidin-1-yl] m ethyl 1-2-m ethyl 1-6-n-itro-2,3 dihydroimidazo [2,1-b] oxazole [2478] A mixture of 2-chloro-4-nitro-1 H-imidazole (1.5 g, 10.17 mmol), 4- (4-chlorobenzyloxy) -1- (2-methyloxyran-2-ylmethyl) piperidine (2.5 g, 8, 45 mmol), sodium hydrogen carbonate (0.86 g, 10.24 mmol) and ethanol (15 ml) was stirred at reflux for 15 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) giving 2- [4- (4-chlorobenzyl) oxipiperidin-1-yl] m-ethyl-2-methyl l-6-n itro-2,3

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613/854 dihydroimidazo [2,1-b] oxazole (662 mg, 16% yield) as a white powder. [2479] Melting point 129-130 ° C.

Example 242

Preparation of 2- {4- [N- (4-chlorophenyl) -N-methyl] aminopiperidin-1-yl} methyl-2-methyl-6-nitro2,3-dihydroimidazo [2,1-b] oxazole [2480] A mixture of 2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (350 mg, 1.61 mmol), 4- [N- (4-chlorophenyl) -Nmethylamino] piperidine (373 mg, 1.66 mmol) and DMF (15 ml) was stirred at 70 ° C for 5 hours. To the reaction mixture, sodium hydride (77 mg, 1.93 mmol) was added, followed by stirring for 1 hour with cooling in an ice bath. The reaction mixture was poured into ice water and extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, washed with a saturated saline solution, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 1/1) giving 2- {4- [N- (4-chlorophenyl) N-methyl] aminopiperidin-1-yl } methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (307 mg, 47% yield) as a light yellow powder.

[2481] Melting point 186-187.8 ° C.

[2482] Using 4- (4-trifluoromethoxybenzyl) pipendin, 4- (4-trifluoromethylbenzyl) piperidine, 4- (4-chlorobenzyl) piperidine and 4- (chlorobenzoyl) piperidine, compounds of Examples 243 to 246 were obtained in the same way as in Example 242.

Example 243 2-methyl-6-nitro-2- [4- (4-trifluoromethoxybenzyl) pipendin-1-yl] methyl-2,3-dihydroimidazo [2,1b] oxazole [2483] Melting point 143.5-145 ° C.

Example 244

2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzyl) piperidin-1-yl] methyl-2,3-dihydroimidazo [2,1 b] oxazole [2484] Melting point 125-126 ° C .

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Example 245

2- [4- (4-chlorobenzyl) piperidin-1-yl] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2485] Melting point 109-110.5 ° C

Example 246 2- [4- (4-chlorobenzoyl) piperidin-1-yl] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2486] Melting point 165-167 ° C.

Example 247

Preparation of 2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzoyl) piperidin-1-yl] methyl-2,3dihydroimidazo [2,1-b] oxazole [2487] A mixture of 2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (80 mg, 0.37 mmol), 4- (4-trifluoromethylbenzoyl) pipendin (95 mg, 0.37 mmol), sodium acetate ( 150 mg, 1.83 mmol) and DMF (2 ml) was stirred at 80 ° C overnight. The reaction mixture was poured into water, and extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, washed with a saturated saline solution, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / nhexane = 1/1) giving 2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzoyl) piperidin-1-yl] methyl2,3-dihydroimidazo [2,1-b] oxazole (46 mg, 29% yield) as a white powder.

[2488] Melting point 172-174 ° C.

[2489] Using corresponding starting materials, the compound of Example 248 was obtained in the same manner as in Example 247.

Example 248 2-methyl-6-nitro-2- [4- (4-trifluoromethoxybenzoyl) pipendin-1-yl] -2,3-dihydroimidazo [2,1b] oxazole [2490] Melting point 165-167 ° C.

Example 249

Preparation of (S) -2- [4- (3,4-dichlorobenzioxy) piperidin-1-i Imethyl] -2-methyl-6-n-itro-2,3dihydroimidazo [2,1- b] oxazole [2491] (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in

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Example 12 (396 mg, 1.82 mmol) and 4- (3,4-dichlorobenzyloxy) piperidine (614 mg, 2.36 mol) in DMF (15 ml) were stirred at 70-75 ° C for 4 hours. The reaction mixture was allowed to return to room temperature, poured into water, extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving a yellow oil.

[2492] The yellow oil was dissolved in DMF (15 ml). Sodium hydride (87 mg, 2.18 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and crystallized from methylene chloride-diisopropyl ether giving (S) -2- [4- (3, 4dichlorobenzyloxy) piperidin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (431 mg, 44% yield) as a white powder.

[2493] MS441 (M ⁺ ) [2494] Melting point 132.0-136.0 ° C.

Example 250

Preparation of (S) - [1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] - (4-fluoromethoxyphenyl) methanone [2495] Using (R) -2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (1.0 g, 4.6 mmol) and 4- (4-trifluoromethoxybenzoyl) pipendin (1.3 g, 4.8 mmol) (S) - [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4 was obtained -il] - (4-fluoromethoxyphenyl) methanone (771 mg, 37% yield) as a light yellow powder.

[2496] Melting point 113.0-115.0 ° C.

Example 251

Preparation of (S) -1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl) piperidinPetition 870190039560, of 26/04/2019, p. 624/876

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Ethyl 4-carboxylate [2497] 2-chloro-4-nitro-1 H-imidazole (3.7 g, 25.1 mmol), (S) -1- (2-methyloxyran-2ylmethyl) piperidine-4-carboxylate tert-butyl (4.8 g, 21.1 mmol) and sodium hydrogen carbonate (2.2 g, 25.1 mmol) in ethanol (25 ml) were stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/1) and crystallized from diethyl ether giving (S) -1- (2-methyl-6-nitro-2 , 3diidroimidazo [2,1-b] oxazol-2-ylmethyl) terp-butyl piperidine-4-carboxylate (1.4 g, 20% yield) as a white powder.

[2498] Melting point 101.0-103.0 ° C.

Example 252

Preparation of (S) -2-methyl-6-nitro-2- [4- (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridin1 -i Im ethyl] -2,3-dihydroim idazo [2 , 1-b] oxazole [2499] 4- (4-trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridine (0.985 g, 4.05 mmol) and (R) -2-chloro-1- (2-methyloxyran -2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.839 g, 3.86 mmol) was added to DMF (15 ml), and the solution was stirred at 60 ° C for 8 hours. The reaction mixture received the addition of water and was extracted with ethyl acetate. The organic phases were washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 4/1) giving an oil. The oil was dissolved in DMF (20 ml), and sodium hydride (94 mg, 2.35 mmol) was added with cooling in an ice bath, followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography

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617/854 silica gel (n-hexane / ethyl acetate = 1/1) giving (S) -2-methyl-6-nitro-2- [4- (4trifluoromethoxyphenyl) -1,2,3,6-tetrahydropyridine -l -ylmethyl] -2,3-dihydroimidazo [2,1 -b] oxazole (0.192 g, 23% yield) as a light yellow solid.

[2500] ¹ H NMR (CDCb) δ ppm:

[2501] 1.68 (3H, s), 2.46 - 3.39 (8H, m), 3.95 (1H, d, J = 10.2 Hz), 4.49 (1H, br),

5.98 (1H, s), 7.16 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.3 Hz), 7.53 (1H, s).

Example 253

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethylphenoxy) piperidin-1-yl] propan-2-ol [2502] (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (500 mg, 2.30 mmol) and 4- (4-trifluoromethylphenoxy) pipendin (730 mg, 3 , 0 mmol) in DMF (10 ml) were stirred at 70-75 ° C for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving (S) -1- (2-chloro-4-nitroimidazole- 1-yl) -2-methyl3- [4- (4-trifluoromethylphenoxy) piperidin-1-yl] propan-2-ol (1.06 g, 99% yield) as a yellow oil.

[2503] ¹ H NMR (CDCb) δ ppm:

[2504] 1.14 (3H, s), 1.80 - 2.04 (4H, m), 2.38 (1H, d, J = 14.0 Hz), 2.48 - 2.68 (2H ,

m), 2.52 (1H, d, J = 14.0 Hz), 2.77 - 2.95 (2H, m), 3.73 (1H, s), 4.01 (2H, s), 4.39 - 4.46 (1H, m), 6.93 - 6.97 (2H, m), 7.49 - 7.55 (2H, m), 8.08 (1H, s).

Example 254

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethylbenzyloxy) piperidin-1-yl] propan-2-ol [2505 ] (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (700 mg, 3.22 mmol) and 4- (4-trifluoromethylbenzyloxy) pipendin (1.09 g, 4.86 mol) in DMF (10 ml) were stirred at 70-75 ° C for 4 hours. The reaction mixture was allowed to return to room temperature, poured into water and extracted with

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[2506] ¹ H NMR (CDCb) δ ppm:

[2507] 1.12 (3H, s), 1.61 -1.78 (2H, m), 1.88-1.96 (2H, m), 2.32 (1H, d, J = 13, 9

Hz), 2.35 - 2.56 (2H, m), 2.47 (1H, d, J = 13.9 Hz), 2.72 - 2.81 (1H, m), 2.86 - 2 , 95 (1H, m), 3.44 - 3.51 (1H, m), 3.63 (1H, bs), 3.97 (2H, s), 4.59 (2H, s), 7, 43 - 7.47 (2H, m), 7.58-7.62 (2H, m), 8.05 (1H, s).

[2508] Using corresponding starting materials, compounds of Examples 255 to 260 shown in the following table were obtained in the same manner as in Example 254.

Table 13

R

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R Ή NMR (CDClj) í Rend. Ξ & 5 ' 4Ό CF j 1.13 (3H _± b), 1.77'1.89 (2 «, m), m), 2.37 (1«, d, J = 13.9H2Á 2.45-2.67Í2H, m>, 2, È1 (1H, d, α = 18.9Η? λ £ .76'2.95 (2 «, mi ₍ 3.71 (1H, b), 4.00 (2«, é), 4.17'4.34 (111, m), 6.85-6.91 (2H , ra). 7, H'7.15 (2H, ¹ m), 6.07 (1 «, b). ¹ 99 £ 56 4 Cl 1.13 (3 «, a), 1.73-1.8 8 (2H, m), 1.91'2.02 (2«, m), 2.36 (1 «, d, J = 13.9Hz), 2.4 4 ' 2. E 3 (2 «, m), 2.Í0CLH, d, J = J3.9« b), £ .76 * 2.95 (2 «, m), 3.64 (1«, s), 3.9 & (£ H , s), 4.26 * 4.35 (1 «, m), 6.79 6.86 (2«, m), 7.18'7.26 (2 «, ín), 8.06 (1« e). 99 2d 7 4CN 1JA (3H, í), 1.81-1.92 (2 «, m), 1.95-2.03 (211, ul), 2.36 (1«, d, J = 18.8Hz), 2.47-2 6 &<2H, mXí.SltlH. d, J-13.9HÍ), 2.77-2.94 (2 «, 3.53 (1H, s), 4.00Í2H, _£ ), 4.4 0 * 4.47 (1«, m), 6.90-8.56 (2 «, m) , 7.63'7.60 (2 «, m), 8.06 (1H, s). 99 258 3-CF _a 1.14Ϊ3Η, e), 1.B1-1.51C2H, in), 1.94-2.02 (211, m), 2.37 (111. d, J-l3.9Hz \ 2.47'2.ββ (2Η. Te), 2.61ÜH, d, J = J3,9He). 2.77-2.S7 (2H, m), 3.61 {1H, s), 3. & 9Í2H, s), 4.38 · 4 · 44 <1Η, m)> 7.04-742Í2H, m), 7.18 * 7122 (1 «, m). 7.35'7.42 (1 «. Ra). S.O7 (1H. S). 95

, ϊίκρρία R Ή NMR (CDCij) í 259 0CF _± 1 ₊ 12 (3H, s), 1.6 € 'J.76 (2H, m), 1.86-1.95 (2H _f m), 2.32 (1H, d, J-13.9H2), 2.36- 2.66 (2 ^ 2.46 (lH _r d _r J = 13.9Hz) _t 2.72 2.S2 (1H, m). 2.65-2 96 (111. m), 3.42-3.49 (111, 3.69Í1H, s ), 4.O2C2H. &), 4.52 (2H. 6>, 7.17'7.21Í2H. M), 7.36-7.39 (211. M), 8.06 (111, f). 260 Cl 1.10 (3H, s), 1.65'1.74 (2 «, m), 1.85-1.92 (211, m), 2.31 (111, d. J = I3.9Hi), 2.3S'2.54 (2H, m ), 2.46C1H, d, J-13.9Hz), 2.71 * 2.79 (1H, m), 2.84'2.95 (1 «, iti), 3.38 * 3.48 (1«. M). 3.72 (1 «. S), 3.96 (2«, s), 4.48 (2 «. &), 7.23-7.32 (211, m), 8.05 (1«, s).

Example 261

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (3-phenyl-2-propenyloxy) piperidin-1-yl] -propan- 2-ol [2509] Using prepared (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole

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620/854 in Example 12 (0.198 g, 0.910 mmol) and 4- (3-phenyl-2-propenyloxy) piperidine (0.198 g, 0.910 mmol) gave (S) -1- (2-chloro-4-nitroimidazole -1-yl) -2-methyl-3- [4- (3-phenyl-2propenyloxy) piperidin-1-yl] propan-2-ol (0.192 g, 49% yield) as a brown oil in the same way as in Example 254.

[2510] ¹ H NMR (CDCb) δ ppm:

[2511] 1.12 (3H, s), 1.55 - 1.98 (4H, m), 2.28 - 2.94 (6H, m), 3.41 - 3.49 (1H, m) ,

3.62 (1H, br), 3.95 (2H, s), 4.16 (1H, d, J = 6.0 Hz), 4.17 (1H, d, J = 6.0 Hz), 6.28 (1H, ddd, J = 6.0 Hz, 6.0 Hz, 15.9 Hz), 6.60 (1H, d, J = 15.9 Hz), 7.21 -7.42 ( 5H, m), 8.05 (1H, s).

Example 262

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3- {4- [3- (4-chlorophenyl) -2propenyloxy] piperidin-1-yl} -2-methylpropan- 2-ol [2512] Using (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.217 g, 1.00 mmol) and 4- [3- ( 4-chloro-phenyl) -2-propenyloxy] piperidine (0.250 g, 0.995 mmol) (S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- {4- [3- (4chlorophenyl) -2-propenyloxy] piperidin-1-yl} -2-methylpropan-2-ol (0.263 g, 56% yield) as a brown liquid in the same manner as in Example 254.

[2513] ¹ H NMR (CDCb) δ ppm:

[2514] 1.12 (3H, s), 1.55 - 2.01 (4H, m), 2.28 - 2.99 (6H, m), 3.40 - 3.51 (1H, m) ,

3.60 (1H, br), 3.96 (2H, s), 4.13 - 4.16 (2H, m), 6.20 - 6.31 (1H, m), 6.56 (1H, d, J = 15.7 Hz), 7.19 - 7.34 (4H, m), 8.05 (1H, s).

Example 263

Preparation of (S) -2- {4- [3- (4-chlorophenyl) propoxy] piperidin-1-iImethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2515] (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in

Example 12 (0.103 g, 0.473 mmol) and 4- [3- (4-chlorophenyl) propoxy] piperidine (0.109 g, 0.430 mmol) were dissolved in DMF (10 ml), and the solution was stirred at 60 ° C for 4 hours. The reaction mixture received the addition of water and extracted with ethyl acetate. The organic phase was combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated

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621/854 under reduced pressure. The residue was purified by means of column chromatography on silica gel (n-hexane / ethyl acetate = 2/3) giving an oil. The oil was dissolved in DMF (2 ml). Sodium hydride (15 mg, 0.375 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 3 hours. To the reaction mixture, water was added, and the precipitates were removed by filtration, purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 6/1) and then recrystallized from ethyl acetate. / nhexane = 1/3 (6 ml) giving (S) -2- {4- [3- (4-chlorophenyl) propoxy] piperidin-1-ylmethyl} -2-methyl6-nitro-2,3-dihydroimidazo [2 , 1-b] oxazole (36 mg, 19% yield) as a white powder.

[2516] Melting point 88.8-91.9 ° C.

Example 264

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3- {4- [2- (4-chlorophenyl) ethoxy] piperidin1 -yl} -2-methyl-propan-2- ol [2517] Using (R) -2-chloro-1 - (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.076 g, 0.350 mmol) and 4- [2- (4-chlorophenyl) ethoxy] piperidine (0.080 g, 0.334 mmol) gave (S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- {4- [2- (4 chlorophenyl) ethoxy] piperidin-1-yl} -2-methyl-propan-2-ol (0.109 g, 71% yield) as a light yellow oil in the same manner as in Example 254.

[2518] ¹ H NMR (CDCb) δ ppm:

[2519] 1.10 (3H, s), 1.51 - 1.72 (2H, m), 1.78 - 1.92 (2H, m), 2.24 -2.50 (4H, m) ,

2.55-2.88 (4H, m), 3.29 - 3.39 (1H, m), 3.58-3.66 (3H, m), 3.94 (2H, s), 7, 15 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz), 8.04 (1H, s).

Example 265

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- {4- [2- (4trifluoromethylphenyl) ethoxy] piperidin-1-yl} propan-2- ol [2520] Triphenyl- (4-fluoromethylbenzyl) phosphonium bromide (3.00 g, 5.98 mmol) was dissolved in DMSO (50 ml). Sodium hydride (0.239 g, 5.98 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 1 hour. A solution of 4Petition 870190039560, of 04/26/2019, p. 630/876

622/854 benzyl formyloxypiperidine-1-carboxylate (1.497 g, 5.69 mmol) in DMSO (10 ml) by dripping, followed by stirring at 60 ° C for 7 hours. The reaction mixture received the addition of water and was extracted with ethyl acetate twice. The organic phases were combined, washing with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 4/1) and then purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9 / 1) giving benzyl 4- [2- (4trifluoromethylphenyl) vinyloxy] piperidin-1-carboxylate as a colorless oil. [2521] The resulting benzyl 4- [2- (4-trifluoromethylphenyl) vinyloxy] piperidin-1-carboxylate was dissolved in ethanol (10 ml) and reduced by catalytic hydrogenation over 10% Pd / C (90 mg) at room temperature under atmospheric pressure. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure giving 4- [2- (trifluoromethylphenyl) ethoxy] pipendin as a brown liquid. [2522] Using the resulting 4- [2- (trifluoromethylphenyl) ethoxy] pipendin and (R) -2chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.184 g, 0.844 mmol) (S) -1- (2-chloro-4-nitroimidazol-1 -yl) -2-methyl-3- {4- [2- (4trifluoromethylphenyl) ethoxy] piperidin-1-yl} propan -2-ol (0.088 g, 3% yield) as a brown oil in the same manner as in Example 254.

[2523] ¹ H NMR (CDCb) δ ppm:

[2524] 1.10 (3H, s), 1.49 - 1.92 (4H, m), 2.24 - 2.81 (6H, m), 2.92 (2H, t, J = 6, 8

Hz), 3.30 - 3.35 (1H, m), 3.65 (2H, t, J = 6.8 Hz), 3.94 (2H, s), 7.34 (2H, d, J = 8.2 Hz), 7.54 (2H, d, J = 8.2 Hz), 8.04 (1H, s).

Example 266 Preparation of (S) -1 - (2-chloro-4-nitroim idazol-1-yl) -2-methyl-3- [4- (4trifluoromethoxyphenylamino) piperidin-1-yl] propan-2-ol [2525] Using (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 and N- (piperidin-4-yl) -4-fluoromethoxyaniline was obtained (S ) -1- (2-chloro-4nitroim idazol-1-yl) -2-methyl-3- [4- (4-trifluoromethoxyphenylamino) pipendin-1-yl] propan-2-ol (1.36 g, yield 88%) as a yellow oil in the same way as in the

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623/854

Example 254.

[2526] ¹ H NMR (CDCb) δ ppm:

[2527] 1.13 (3H, s), 1.41 -1.57 (2H, m), 2.03-2.08 (2H, m), 2.34 (1H, d, J = 13, 9

Hz), 2.49 - 2.59 (3H, m), 2.65 - 2.77 (2H, m), 3.08 - 2.16 (2H, m), 3.24 - 3.41 ( 1H, m), 3.97 (2H, s), 6.47 - 6.55 (2H, m), 6.98 - 7.04 (2H, m), 8.05 (1H, s).

[2528] Using corresponding starting materials, compounds of Examples 267 to 269 shown in the following table were obtained in the same manner as in Example 266.

Table 15

ΕχβψΐΌ R Rend. (¾) Ή NMR CCDCU 5 267 GL 99 The). 1.40'1.53 (3H _r m), 2.00-2.06Ϊ2Η, m), 2.35Ϊ1Η, d, J = 18.9Hi), 2.45 · 2.59 (3Η, πΐ), 2.71-3.01 (211, m), 3.18ÜH , br), 3-48-3.68 (2H, m), 3.97Ϊ2Η, a), 6.47'6.54 (2H, m), 7, Q7-7.14 (2H, jn), 8.05 (1H, a). 266 CF, 99 1.14 (3H, 6). 1.42Ί.β9 (2Η, 2.03-2.08Í2H, m), 2.35 (111, d. J = 13.9Hz \ 2.49-2.60Ϊ2Η, m), 2.5O (1H, d. J = 13.9H &), 2.74 2.9 & (2H, m), 3.31-3.39Í1H, m), 3.EK1H, a), 3.87C1H, d, J = S.3Hí) 3.97Í2H, e), 6.E8Í2H, d, J = 8.7Ha), 7.39 (211, d, J-8.7Hz) _h 0, O6 (1H, s). 269 CN 99 1.13 (3H. A), 1.40-1.53Í2H, m), 2.00-2O6 (2H, m), 2.35Í1H, d, J = 13.9Hs), 2.46'2.59 (2H, m), 2.49 (111, d. 0 = 13.93 ^), 2.71'3.01 (2H, m), 3.18Ϊ1Η, br), 3.48-3.58Í2H, m), 3.97 (2H, s), 6.51-6.57 (2H _r m), 7.3 & -7.44Ϊ2Η, m), 8, O5 (1H, β).

Example 270

Preparation of (S) -1 - (4-piperidinopiperidin-1-yl) -3- (2-chloro-4-nitroimidazol-1-yl) -2-methylpropprop-2-ol [2529] (R) -2- chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.500 g, 2.29 mmol) and 4-piperidinopiperidine (0.425 g, 2.53 mmol) were dissolved in DMF (5 ml), and the solution was stirred at 70 ° C for 5 hours. The mixture

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624/854 of reaction received the addition of water and was extracted with ethyl acetate twice. The organic phases were combined, washing with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/2) using basic silica gel giving (S) -1 - (4-piperidinopiperidin-1-yl) -3- (2-chloro-4-nitroimidazole-1-yl) -2-methyl-propan2-ol (0.656 g, 74% yield) as a brown oil.

[2530] ¹ H NMR (CDCb) δ ppm:

[2531] 1.11 (3H, s), 1.38 - 1.89 (10H, m), 2.18 - 2.55 (9H, m), 2.70-2.81 (1H, m) ,

2.89 - 3.01 (1H, m), 3.67 (1H, br), 3.94 (1H, s), 8.05 (1H, s).

Example 271

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3 - {[4- (4trifluoromethoxyphenyl) sulfanyl] piperidin-1-yl) propan-2-ol [ 2532] Using (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 and 4- [4- (trifluoromethoxy) phenylsulfanyl] pipendin obtained (S) -1 - (2-chloro4-nitroimidazol-1-yl) -2-methyl-3 - {[4- (4-trifluoromethoxyphenyl) sulfanyl] pipendin-1-yl} propan-2ol (3.4 g, 99% yield) as a yellow oil in the same way as in Example 270.

[2533] ¹ H NMR (CDCb) δ ppm:

[2534] 1.11 (3H, s), 1.58 - 1.73 (2H, m), 1.91 -1.99 (2H, m), 2.32 (1H, d, J = 13, 9

Hz), 2.41 -2.50 (2H, m), 2.46 (1H, d, J = 13.9 Hz), 2.75 -3.09 (4H, m), 3.97 (2H , s), 7.11 - 7.17 (2H, m), 7.36 - 7.53 (2H, m), 8.04 (1H, s).

Example 272

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethoxybenzyl) piperidin-1-yl] propan-2-ol [2535] Using 4- (4-trifluoromethoxybenzyl) pipendin and (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12, (S) -1- (2-chloro-4-nitroimidazole-) was obtained 1 -yl) -2-methyl-3- [4- (4-trifluoromethoxybenzyl) piperidin-1-yl] propan-2ol (crude) as a yellow oil in the same manner as in Example 270.

[2536] ¹ H NMR (CDCb) δ ppm:

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625/854 [2537] 1.10 (3H, m), 1.22 -1.71 (5H, m), 2.26-2.55 (6H, m), 2.66-2.96 (3H , m),

3.94 (2H, s), 7.09-7.18 (4H, m), 8.06 (1H, s).

[2538] Using corresponding starting materials, compounds of Examples 273 and 274 shown in the following table were obtained in the same manner as in Example 272.

Table 16

EMSnçlc B Rend. (¾) 'Ή ΈΜΝ ÍCDCl _a ) $ 273 4-Cr ₃ 56 1.10Í3H, s) j 1.14Ί.3B (2H, m), 1.47-1.64Í8H, m), 2.29Í1H, d, J = 13.9H2), 2.30-2.40 (2H, m), 2.43 (1H, d, J = 13.9Hx), 2.60 (2H, d, J = 6.5Hz), 2.69 (1H _I d, J = 11.7Hz). 2.90Ϊ1Η, d, J = 11.7Hz), 3.74 (1H, br) 3.94 (2H, b), 7-22-7.26Ϊ2Η, m), 7.52-7.54Í2H, m), 8.05 (lH, s). 274 4-Cl 65 1.10 (3H, s) j 1.14-1.Ê3 (& H, m), 2.26 * 2.52 (? H _f m), 2.68 (1H, d, 2.90Í1H, d. J-11.5Hz), 3.94Í2H, s) , 7.00-7.0B (2H. M), 7.20 * 7.29H2H. m), 8.0ÊC1H, s).

Example 275

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- (4-pheni 1-1,2,3,6tetrahydropyridin-1-yl) propan-2 -ol [2539] 4-Phenyl-1,2,3,6-tetrahydropyridine hydrochloride (0.495 g, 2.53 mmol) was added to a sodium hydroxide solution, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.5 g, 2.29 mmol) and DMF (5 ml) were added to the residue, followed by stirring at 70 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washing with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under

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626/854 reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 2/1) giving (S) -1 - (2-chloro-4-nitroim idazole -1 -yl) -2methyl-3- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) propan-2-ol (0.492 g, 57% yield) as a yellow oil.

[2540] ¹ H NMR (CDCb) δ ppm:

[2541] 1.17 (3H, s), 2.47 (1H, d, J = 13.9 Hz), 2.58-2.64 (3H, m), 2.78-3.00 (2H ,

m), 3.27 - 3.40 (2H, m), 3.62 (1H, br), 4.01 (2H, s), 6.02 - 6.05 (1H, m), 7.23 - 7.41 (5H, m), 8.07 (1H, s).

Example 276

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- (4-phenyl Ipiperid in-1 yl) propan-2-ol [2542] 4-phenylpiperidine hydrochloride (0.522 g, 2.64 mmol) to a sodium hydroxide solution, and extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4nitroimidazole prepared in Example 12 (0.5 g, 2.29 mmol) and DMF (5 ml) were added to the residue, followed by stirring at 70 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washing with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (nhexane / ethyl acetate = 2/1) giving (S) -1- (2-chloro-4-nitroim idazol-1-yl) -2-methyl -3- (4-phenylpiperidin-1-yl) propan-2-ol (0.703 g, 81% yield) as a yellow oil.

[2543] ¹ H NMR (CDCb) δ ppm:

[2544] 1.14 (3H, s), 1.76 -1.89 (4H, m), 2.36 (1H, d, J = 13.9 Hz), 2.48-2.61 (4H ,

m), 2.75-2.89 (1H, m), 2.98 - 3.09 (1H, m), 3.75 (1H, br), 3.98 (2H, s), 7.18 -7.35 (5H, m), 8.08 (1H, s).

Example 277

Preparation of (S) -1 - (2-chloro-4-nitroimidazole-1-yl) -2-methyl 1-3- [4- (4trifluoromethylphenyl) piperidin-1-yl] propan-2-ol

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627/854 [2545] (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.329 g, 1.51 mmol) and 4- (4-trifluoromethylphenyl) piperidine (0.40 g, 1.66 mmol) were dissolved in DMF (5 ml), followed by stirring at 70 ° C for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washing with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 2/1) giving (S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl -3- [4- (4-trifluoromethylphenyl) piperidin-1-yl] propan-2-ol (0.361 g, 54% yield) as a brown oil.

[2546] ¹ H NMR (CDCb) δ ppm:

[2547] 1.13 (3H, s) 1.71 -1.93 (4H, m), 2.36 (1H, d, J = 14.0 Hz), 2.48 - 2.65 (4H,

m), 2.77 - 2.90 (1H, m), 3.01 - 3.14 (1H, m), 3.64 (1H, br), 3.99 (2H, s), 7.32 (2H, d, J = 8.1 Hz), 7.57 (2H, d, J = 8.1 Hz), 8.07 (1H, s).

Example 278

Preparation of (S) - {1 - [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperidin4-yl} ter-butyl carbamate [2548] Using (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 and ter-butyl piperidin-4-ylcarbamate (S) - {1- [3- (2- chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] -piperidin-4-yl} tert-butyl carbamide (92% yield) a yellow oil in the same manner as in Example 277. [ 2549] ¹ H NMR (CDCb) δ ppm:

[2550] 1.11 (3H, s), 1.32 - 1.51 (2H, m), 1.44 (9H, m), 1.90 - 1.96 (2H, m), 2.32 (1H, d, J = 13.9 Hz), 2.39-2.55 (2H, m), 2.46 (1H, d, J = 13.9 Hz), 2.67-2.96 ( 3H, m), 3.44 (1H, br), 3.59 (1H, s), 3.96 (2H, s), 8.05 (1H, s).

Example 279

Preparation of (S) - {1 - [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methyl-propyl] piperidin4-yl} -N- [2- (4-trifluoromethylphenyl) ) ethyl] ter-butyl carbamate [2551] Using (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.332 g, 0.891 mmol) and piperidin-4 -il-N- [2- (4

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628/854 trifluoromethylphenyl) ethyl] ter-butyl carbamate (0.194 g, 0.891 mmol) gave (S) - {1 [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2 -methyl-propyl] piperidin-4-yl} -N- [2- (4trifluoromethylphenyl) ethyl] ter-butyl carbamate (0.370 g, 70% yield) as a light yellow oil in the same manner as in Example 277.

[2552] ¹ H NMR (CDCb) δ ppm:

[2553] 1.12 (3H, s), 1.49 (9H, s), 1.55 - 1.80 (4H, m), 2.17 -2.57 (4H, m), 2.70 -

2.98 (4H, m), 3.21 - 3.30 (2H, m), 3.50 (1H, s), 3.95 (2H, s), 7.31 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.05 (1H, s).

Example 280

Preparation of (S) -2-methyl-6-nitro-2- [4- (4-trifluoromethylphenoxy) piperidin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole [2554] (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethylphenoxy) piperidin-1-yl] propan-2-ol prepared in Example 253 (1.06 g, 2, 3 mmol) was dissolved in DMF (15 ml). Sodium hydride (110 mg, 2.76 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 5/1) and crystallized from methylene chloride-diisopropyl ether giving (S) -2-methyl-6-nitro- 2- [4- (4trifluoromethylphenoxy) pipendin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole (431 mg, 44% yield) as a white powder.

[2555] MS427 (M + 1) ⁺ [2556] Optical purity 97.8% ee

[2557] [a] d ²⁷ = -2.07 ° (concentration: 1.064, CHCb) [2558] ¹ H NMR (CDCb) δ ppm:

[2559] 1.61 (3H, s), 1.67 - 1.92 (4H, m), 2.41 - 2.51 (1H, m), 2.57 (1H, d, J = 14, 9

Hz), 2.58 - 2.67 (1H, m), 2.88 (1H, d, J = 14.9 Hz), 2.74 - 2.98 (2H, m), 3.91 (1H , d, J = 9.7 Hz), 4.31 (1H, d, J = 9.7 Hz), 4.28 - 4.36 (1H, m), 6.91 (2H, d, J = 8.7 Hz), 7.51

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629/854 (2H, d, J = 8.7 Hz), 7.54 (1H, s).

Example 281

Preparation of (S) -2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzyloxy) pipendin-1-methyl] -2,3 dihydroimidazo [2,1-b] oxazole [2560] (S) -1 - (2-chloro-4-nitroim idazol-1 -yl) -2-methyl-3- [4- (4trifluoromethylbenzyloxy) piperidin-1-yl] propan-2-ol prepared in Example 254 (1.36 g, 2 , 8 mmol) was dissolved in DMF (15 ml). Sodium hydride (134 mg, 3.36 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and crystallized from methylene chloride-diisopropyl ether giving (S) -2-methyl-6-nitro-2- [4 (4-trifluoromethylbenzyloxy) pipendin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole (431 mg, 44% yield) as a powder White.

[2561] MS440 (M-1) ⁺ [2562] Melting point 91 -92 ° C [2563] Optical purity 99.6% ee

[2564] [oc] d ²⁷ = -8.63 ° (concentration: 1.066, CHCb) [2565] ¹ H NMR (CDCb) δ ppm:

[2566] 1.44 - 1.66 (2H, m), 1.60 (3H, s), 1.71 - 1.85 (2H, m), 2.28 - 2.38 (1H, m) ,

2.44 - 2.56 (1H, m), 2.52 (1H, d, J = 14.9 Hz), 2.72 - 2.81 (1H, m), 2.84 (1H, d, J = 14.9 Hz), 2.87 - 2.94 (1H, m), 3.33 - 3.41 (1H, m), 3.88 (1H, d, J = 9.6 Hz), 4.31 (1H, d, J = 9.6 Hz), 4.54 (2H, s), 7.41 - 7.44 (2H, m), 7.52 (1H, s), 7.56 - 7.60 (2H, m).

Example 282

Preparation of (S) -2- [4- (4-trifluoromethoxyphenyl) aminopiperidin-1-yl] methyl-2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazole [2567] Using (S) -1 - (2-chloro-4-nitroim idazol-1-yl) -2-methyl ethyl [3- (4- 4trifluoromethoxyphenylamino) piperidin-1-yl] propan-2-ol prepared in Example 266 obtained

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630/854 se (S) -2- [4- (4-trifluoromethoxyphenyl) aminopiperidin-1-yl] methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole (73% yield ) as a white powder in the same way as in Example 281.

[2568] Melting point 107.5-109.0 ° C [2569] MS 441 (M ⁺ ) [2570] Optical purity 99.8% ee

[2571] [a] d ²⁷ = 19.19 ° (concentration: 1.006, CHCb).

Example 283

Preparation of (S) - [1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2ylmethyl) piperidin-4-yl] ter-butyl carbamate [2572] Using ( S) - {1 - [3- (2-chloro-4-nitro-imidazol-1-yl) -2-hydroxy-2-methylpropyl] piperidin-4-yl} ter-butyl carbamate prepared in Example 278 was obtained ( S) - ter-Butyl [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4-yl] carbamate (49% yield) as a white powder in the same way as in Example 281.

[2573] MS381 (M ⁺ ) [2574] Melting point 158.5-160.7 ° C.

Example 284

Preparation of (S) - [1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2ylmethyl) piperidin-4-yl] -N- [2- (4-trifluoromethylphenyl) ) ethyl] ter-butyl carbamate [2575] Using (S) - {1 - [3- (2-chloro-4-nitro-imidazol-1-yl) -2-hydroxy-2-methylpropyl] piperidin-4- il} -N- [2- (4-trifluoromethylphenyl) ethyl] ter-butyl carbamate prepared in Example 279 (0.37 g, 0.627 mmol) gave (S) - [1- (2-methyl-6-nitro- 2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperidin-4-yl] -N- [2- (4-trifluoromethylphenyl) ethyl] tert-butyl carbamate (0.211 g, 63% yield) as a light yellow powder in the same way as in Example 281.

[2576] Melting point 206.8-208.6 ° C.

Example 285

Preparation of (S) -2-methyl-6-nitro-2- {4- [4- (trifluoromethoxyphenyl) sulfanyl] piperidin-1ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole

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631/854 [2577] Using (S) -1 - (2-chloro-4-nitro-imidazol-1-yl) -2-methyl-3 - {[4- (4trifluoromethoxyphenyl) sulfanyl] piperidin-1-yl } propan-2-ol prepared in Example 271 (S) -2-methyl-6-nitro-2- {4- [4- (trifluoromethoxyphenyl) sufanyl] piperidin-1-ylmethyl} -

2,3-dihydroimidazo [2,1-b] oxazole (62% yield) as a white powder in the same manner as in Example 281.

[2578] MS 458 (M ⁺ ) [2579] Melting point 133.0-137.4 ° C.

Example 286

Preparation of (S) -2-methyl-6-nitro-2- [4- (4-trifluoromethoxybenzyl) piperidin-1-yl] methyl-2,3dihydroimidazo [2,1-b] oxazole [2580] Using (S) -1 - (2-chloro-4-nitro-imidazol-1-yl) -2-methyl-3- [4- (4trifluoromethoxybenzyl) piperidin-1-yl] propan-2-ol prepared in Example 272 (S) -2-methyl-6-nitro-2- [4- (4-trifluoromethoxybenzyl) piperidin-1-yl] methyl-2,3dihydroimidazo [2,1-b] oxazole (55% yield) as a powder white in the same way as in Example 281.

[2581] Melting point 111.0-112.5 ° C [2582] Mass spectrum: 440 (M ⁺ ) [2583] Optical purity 99.0% ee

[2584] [oc] d ²⁷ = 5.38 ° (concentration: 1.004, CHCb).

Example 287

Preparation of (S) -2-methyl-6-nitro-2- (4-phenyl-1,2,3,6-tetrahydropyrid in-1-i Imethyl) -2,3 dihydroimidazo [2,1-b] oxazole [2585] (S) -1 - (2-chloro-4-nitro-imidazol-1-yl) -2-methyl-3- (4-pheni 1-1,2,3,6tetrahydropyridin-1-yl) propan-2-ol prepared in Example 275 (0.492 g, 1.31 mmol) was dissolved in DMF (8 ml). Sodium hydride (63 mg, 1.57 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture. After extraction with ethyl acetate, the organic phase was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography over

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632/854 silica gel (n-hexane / acetone = 4/1) and recrystallized from methylene chloride-ethyl acetate giving (S) -2-methyl-6-nitro-2- (4-phenyl-1,2 , 3,6-tetrahydropyrid in-1-i Imethyl) -2,3-dihydroimidazo [2,1-b] oxazole (0.059 g, 13% yield) as a light yellow solid.

[2586] Melting point 200.1 -201 ° C.

Example 288

Preparation of (S) -2-methyl-6-nitro-2- (4-phenylpiperidin-1-ylmethyl) -2,3-dihydroimidazo [2,1 b] oxazole [2587] (S) -1 - (2- chloro-4-nitro-imidazol-1-yl) -2-methyl l-3- (4-phenyl Ipiperid in-1-yl) propan-2ol prepared in Example 276 (0.703 g, 1.86 mmol) was dissolved in DMF (5 ml). Sodium hydride (89 mg, 2.23 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture. The precipitates were removed by filtration, purified by column chromatography on silica gel (n-hexane / acetone = 3/1) and recrystallized from ethyl acetate giving (S) -2-methyl-6-nitro-2- (4-phenylpiperidin1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole (0.230 g, 36% yield) as a white powder.

[2588] Melting point 158.8-163.9 ° C.

[2589] Using corresponding starting materials, compounds of Examples 289 to 294 were obtained in the same manner as in Example 288.

Example 289 (S) -T- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) - [1,4 '] bipiperidinyl [2590] Melting point 163 , 4-164.9 ° C.

Example 290 (S) -2-methyl-6-nitro-2- [4- (4-trifluoromethylphenyl) piperidin-1-ylmethyl] -2,3-dihydroimidazo [2,1 b] oxazole [2591] Melting point 138.7-139.9 ° C.

Example 291 (S) -2-methyl-6-nitro-2- [4- (3-phenyl-2-propenyloxy) piperidin-1-ylmethyl] -2,3-dihydroimidazo [2,1 b] oxazole

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633/854 [2592] Melting point 91.3-92.7 ° C.

Example 292 (S) -2- {4- [3- (4-chlorophenyl) -2-propenyloxy] piperidin-1-ylmethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2593] Melting point 140.6-142.8 ° C.

Example 293 (S) -2-methyl-6-nitro-2- {4- [2- (4-trifluoromethylphenyl) ethoxy] piperidin-1-ylmethyl} -2,3dihydroimidazo [2,1-b] oxazole [2594] Melting point 84.6-86.8 ° C.

Example 294 (S) -2- {4- [2- (4-chlorophenyl) ethoxy] piperidin-1-ylmethyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole [2595] Melting point 92.5-94 ° C.

Example 295

Preparation of (S) - [1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2ylmethyl) piperidin-4-yl] -N-methyl-4-trifluoromethoxyaniline [2596 ] (S) -2- [4- (4-trifluoromethoxyphenyl) aminopipendin-1-yl] methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole prepared in Example 282 (400 mg, 0.90 mmol) was dissolved in methanol (10 ml). A solution of 37% formaldehyde (0.13 ml, 4.52 mmol), sodium cyanotrihydroborate (170 mg, 2.71 mmol) and acetic acid (0.17 ml, 2.71 mmol) was added to the solution. , followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into a saturated solution of sodium hydrogen carbonate and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and recrystallized from methylene chloride-diisopropyl ether giving (S) -N- [1- (2-methyl- 6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4-yl] -N-methyl-4-trifluoromethoxyaniline (309 mg, 78% yield) as light yellow crystals.

[2597] Optical purity 99.9% e.e.

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634/854 [2598] [oc] d ¹⁷ = 7.77 (concentration: 1.042, CHCb) [2599] MS 455 (M ⁺ ) [2600] Melting point 133.2-134.4 ° C.

Example 296

Preparation of (S) -N- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] -N- (4-fluoromethoxyphenyl) acetamide [2601] (S) -2- [4- (4-trifluoromethoxyphenyl) aminopipendin-1-yl] methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole prepared in Example 282 ( 153 mg, 0.35 mmol) was dissolved in methylene chloride (5 ml). Triethylamine (30 μΙ) and acetyl chloride (30 μΙ) were added to the solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from methylene chloride-diisopropyl ether giving (S) -N- [1- (2-methyl- 6-nitro-

2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4-yl] -N- (4trifluoromethoxyphenyl) acetamide (82 mg, 49% yield) as a white powder.

[2602] MS484 (M + 1) ⁺ [2603] Melting point 137.0-138.7 ° C.

Example 297

Preparation of (S) -2- {4-N - [(4-trifluoromethylphenyl) acetyl] aminopiperidin-1-yl} methyl-2-methyl6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2604 ] (S) - [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] ter-butyl carbamate prepared in Example 283 (0 , 1 g, 0.262 mmol) was dissolved in ethanol (4 ml). 6 N hydrochloric acid (3 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride (4 ml) and triethylamine (4 ml) were added to the residue. The resulting mixture was stirred at room temperature for 5 minutes and then concentrated. Toluene (10 ml) was added to the residue. The solution was concentrated to remove water azeotropically. Acid 4 was added to the residue

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635/854 trifluoromethylphenylacetic (0.064 g, 0.315 mmol), methylene chloride (4 ml), triethylamine (0.06 ml, 0.393 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD) (0.065 g, 0.341 mmol), followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride twice. The organic phases were combined, washing with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / acetone = 3/2) and recrystallized from ethyl acetate (3 ml) giving (S) - 2- {4-N - [(4trifluoromethylphenyl) acetyl] aminopipendin-1-yl} methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole (32 mg, 26% yield) as a white powder.

[2605] Melting point 152.7-154.3 ° C.

Example 298

Preparation of 4-trifluoromethylbenzyl (S) - [1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2ylmethyl) piperidin-4-yl] carbamate [2606] (S ) - [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] ter-butyl carbamate prepared in Example 283 (0.300 g, 0.787 mmol) was dissolved in methylene chloride (4 ml). Trifluoroacetic acid (2 ml) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and received the addition of methylene chloride (4 ml) and triethylamine (4 ml). The mixture was stirred at room temperature for 5 minutes and concentrated under reduced pressure. The residue was dissolved in DMF (6 ml). A mixture of 4- (trifluoromethyl) benzyl alcohol (0.166 g, 0.944 mmol) in DMF (4 ml) and 1. T-carbonyldiimidazole (0.153 g, 0.944 mmol) stirred at room temperature for 4 hours was added to the solution. followed by stirring at room temperature overnight and then at 65 ° C for 8 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography

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636/854 on silica gel (n-hexane / acetone = 2/1) and recrystallized from ethyl acetate giving (S) [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1- b] oxazol-2-ylmethyl) piperidin-4-yl] 4-trifluoromethylbenzyl carbamate (0.107 g, 28% yield) as a light yellow powder. [2607] Melting point 141.2-144 ° C.

[2608] Using corresponding starting materials, compounds of Examples 299 and 300 were obtained in the same manner as in Example 298.

Example 299

- (4-trifluoromethylphenyl) piperidin-4-yl (S) - [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperidin-4-yl] carbamate [2609] Melting point 134.4-136.9 ° C.

Example 300 (S) - [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4-yl] 4-trifluoromethoxybenzyl carbamate [2610] Melting point 156.2-158.5 ° C.

Example 301

Preparation of (S) -N- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] -4-fluoromethylbenzylamine [2611] ( S) - ter-Butyl [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] carbamate prepared in Example 283 (0.300 g, 0.787 mmol) was dissolved in methylene chloride (4 ml). Trifluoroacetic acid (2 ml) was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and received the addition of methylene chloride (4 ml) and triethylamine (4 ml). The mixture was stirred at room temperature for 20 minutes and then concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-trifluoromethylbenzaldehyde (0.164 g, 0.945 mmol), sodium cyanotrihydroborate (0.099 g, 1.57 mmol) and acetic acid (0.09 ml, 1.57 mmol) were added, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride. The organic phases were combined, washing with a saturated saline solution, dried over sodium sulfate.

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637/854 sodium and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) and recrystallized from isopropyl alcohol giving (S) -N- [1- (2methyl-6-nitro-2, 3-dihydroim idazo [2,1 -b] oxazol-2-ylmethyl) piperidin-4-yl] -4trifluoromethylbenzylamine (0.078 g, 22% yield) as a light yellow powder. [2612] Melting point 148.6-152.9 ° C.

Example 302

Preparation of (S) -1 - [1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2ylmethyl) piperidin-4-yl] -3- (4-trifluoromethylphenyl) urea [2613] (S) - [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] ter-butyl carbamate prepared in Example 283 (0.300 g, 0.787 mmol) was dissolved in methylene chloride (4 ml). Trifluoroacetic acid (2 ml) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and received the addition of methylene chloride (4 ml) and triethylamine (4 ml). The mixture was stirred at room temperature for 5 minutes and concentrated under reduced pressure. The residue was called residue 1.

[2614] On the other hand, 4- (trifluoromethyl) aniline (0.139 g, 0.865 mmol) and pyridine (0.07 ml, 0.865 mmol) were dissolved in THF (4 ml). Phenyl chloroformate (0.108 ml, 0.865 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 1 hour. The reaction mixture received the addition of water and was extracted with ethyl acetate. The organic phase was washed with water, 10% hydrochloric acid and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure.

[2615] The resulting solid was dissolved in dimethyl sulfoxide (6 ml). Residue 1 was added to the solution, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water, a saturated solution of sodium hydrogen carbonate and a saline solution

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638/854 saturated, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (n-hexane / acetone = 2/1) and recrystallized from isopropyl-n-hexane alcohol (1: 1) (6 ml) giving (S) -1- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperidin-4-yl] -3- (4 -tnfluoromethylphenyl) urea (0.064 g, 17% yield) as a light yellow powder.

[2616] Melting point 136.8-139.9 ° C.

Example 303

Preparation of (S) -2- [4-N- (4-trifluoromethylbenzoyl) aminopiperidin-1-yl] methyl-2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazole [2617] (S ) - [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] ter-butyl carbamate prepared in Example 283 (360 mg, 0 , 92 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and received the addition of methylene chloride (10 ml) and triethylamine (2 ml). 4trifluoromethylbenzoyl chloride (0.3 ml, 1.85 mmol) was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) and crystallized from ethyl acetate-diisopropyl ether giving (S) -2- [4-N- (4-trifluoromethylbenzoyl ) aminopipendin-1yl] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (232 mg, 55% yield) as a white powder.

[2618] MS 454 (M + H) ⁺ [2619] Melting point 170.5-171.7 ° C.

Example 304

Preparation of (S) -N- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] -2- (4-fluoromethylphenyl) ethylamine

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639/854 [2620] (S) - [1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] -N- [2- (4-trifluoromethylphenyl) ethyl] tert-butyl carbamate prepared in Example 284 (0.196 g, 0.354 mmol) was dissolved in methylene chloride (2 ml). Trifluoroacetic acid (1 ml) was added to the solution, followed by stirring at room temperature for 4 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the solution was extracted with methylene chloride twice. The organic phases were combined, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and treated with isopropyl ether giving (S) -N- [1- (2methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl) piperidin-4-yl] -2- (4trifluoromethylphenyl) ethylamine (0.020 g, 12% yield) like a light yellow powder. [2621] Melting point 80.7-84.2 ° C.

Example 305

Preparation of (S) -2-methyl-6-nitro-2- {4- [4- (trifluoromethoxy) benzenesulfinyl] piperidin-1ylmethyl} -2,3-dihydroimidazo [2,1-b] oxazole [2622] (S ) -2-methyl-6-nitro-2- {4- [4- (trifluoromethoxyphenyl) sulfanyl] piperidin-1-ylmethyl} 2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 285 (300 mg, 0.65 mmol) was dissolved in methylene chloride (5 ml). Chloroperbenzoic acid (169 mg, 0.69 mmol) was added to the solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with methylene chloride. The solution was washed with a sodium thiosulfate solution, a saturated sodium hydrogen carbonate solution and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) and crystallized from ethyl acetate-isopropyl ether giving (S) -2-methyl-6-nitro-2- {4- [4- (trifluoromethoxy) benzenesulfinyl] piperidin-1-ylmethyl} -2,3 dihydroimidazo [2,1-b] oxazole (219 mg, 71% yield) as a white powder.

[2623] MS 475 (M + H) ⁺ [2624] Melting point 107-109 ° C.

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640/854

Example 306

Preparation of 2- (4-ter-butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2625] 2-chloro-4-nitro- 1 H-imidazole (3.19 g, 21.6 mmol) and tert-butyl 4- (2-methyloxyran-2-methyl) piperazine-1-carboxylate (5.53 g, 21.6 mmol) and sodium acetate ( 1.95 g, 23.8 mmol) were dissolved in 1-propanol (50 ml), followed by stirring at reflux for 48 hours. The reaction mixture was diluted with methylene chloride. The solution was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and treated with methylene chloride-diisopropyl ether giving 2- (4-ter-butoxycarbonylpiperazin-1-yl) methyl -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole (1.85 g, 23% yield) as a white powder.

[2626] ¹ H NMR (CDCb) δ ppm:

[2627] 1.43 (9H, s), 1.62 (3H, s), 2.45 - 2.68 (5H, m), 2.87 (1H, d, J = 14.9 Hz),

3.30 (4H, br), 3.93 (1H, d, J = 9.7 Hz), 4.30 (1H, d, J = 9.7 Hz), 7.54 (1H, s).

[2628] Using corresponding starting materials, the compound of Example 307 was obtained in the same way as in Example 306.

Example 307 2- [4- (4-cyanophenyl) piperazin-1-yl] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2629] 18% yield [2630 ] ¹ H NMR (CDCb) δ ppm:

[2631] 1.67 (3H, s), 2.60 - 2.80 (3H, m), 2.80 - 3.00 (3H, m), 3.22 (4H, br), 3.97 (1H, d, J = 9.8 Hz), 4.35 - 4.50 (1H, m), 6.78 - 6.85 (2H, m), 7.46 - 7.51 (2H, m ), 7.55 (1H, s).

Example 308

Preparation of 2- [4- (4-trifluoromethylphenyl) piperazin-1-yl] m eti l-2-m eti l-6-n itro-2,3 dihydroimidazo [2,1-b] oxazole [2632] To a solution of 2-chloro-4-nitro-1 H-imidazole (1.59 g, 10.8 mmol) and 1- (2-methyloxyran-2-ylmethyl) -4- (4-trifluoromethylphenyl) piperazine (3.23 g, 10 , 8 mmol) in 1 Petition 870190039560, of 26/04/2019, p. 649/876

641/854 propanol (20 ml), sodium hydrogen carbonate (1.95 g, 23.8 mmol) was added, followed by stirring at reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue received the addition of water and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from methylene chloride-isopropyl ether giving 2- [4- (4-trifluoromethylphenyl) piperazin-1 - yl] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (1.34 g, 29% yield) as a light yellow powder. [2633] MS 411 (M ⁺ ) [2634] Melting point 159-160 ° C.

[2635] Purification by column chromatography on silica gel also gives an intermediate, 2-chloro-1- {3- [4- (4-trifluoromethylphenyl) piperazin-1-yl] -2-hydroxy-2methyl} propyl-4-nitroimidazole (697 mg, 15% yield) as a yellow oil. [2636] ¹ H NMR (CDCb) δ ppm:

[2637] 1.17 (3H, s), 2.32-2.91 (6H, s), 3.26 - 3.31 (4H, m), 4.03 (2H, s), 6.71 (1H,

s), 6.89 - 6.93 (2H, m), 7.45 - 7.51 (2H, m), 8.06 (1H, s).

[2638] Using corresponding starting materials, compounds of Examples 309 to 311 were obtained in the same manner as in Example 308.

Example 309 2- [4- (Biphenyl-4-yl) piperazin-1-yl] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2639] 32% yield melting point 223-227.8 ° C.

Example 310 2- [4- (4-chlorophenyl) piperazin-1-yl] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2640] 14% yield, point melting temperature 196.6-197.3 ° C.

Example 311 2- [4- (4-trifluoromethoxyphenyl) piperazin-1-yl] methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole [2641] 18% yield [2642] ¹ H NMR (CDCb) δ ppm:

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642/854 [2643] 1.61 (3H, s), 2.61 (1H, d, J = 14.8 Hz), 2.65 - 2.73 (2H, m), 2.82 - 2, 95 (2H,

m), 2.93 (1H, d, J = 14.8 Hz), 2.99 - 3.09 (4H, m), 3.94 (1H, d, J = 9.7 Hz), 4, 34 (1H, d, J = 9.7 Hz), 6.78 - 6.86 (2H, m), 7.06 - 7.11 (2H, m), 7.53 (1H, s).

Example 312

Preparation of 1 - [3- (4-ter-butoxycarbonylpiperazin-1-yl) -2-hydroxy-2-methyl] propyl-2-chloro4-nitroimidazole [2644] 2-chloro-4-nitro-1 H-imidazole (863 mg, 5.85 mmol) and tert-butyl 4- (2-methyloxyran-2ylmethyl) piperazine-1-carboxylate (1.5 g, 5.85 mmol) were dissolved in

1- propanol (10 ml), followed by reflux stirring for 6 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 1- [3- (4-ter-butoxycarbonylpiperazin-1-yl) -

2-hydroxy-2-methyl] propyl-2-chloro-4-nitroimidazole (705 mg, 29.8% yield) as a white powder.

[2645] ¹ H NMR (CDCb) δ ppm:

[2646] 1.15 (3H, s), 1.45 (9H, s), 2.35 (1H, d, J = 13.9 Hz), 2.45 - 2.65 (5H, m),

3.25 (1H, s), 3.42 (4H, t, J = 4.3 Hz), 4.00 (2H, s), 8.05 (1H, s).

[2647] Using 2-chloro-4-nitro-1 H-imidazole and tert-butyl 4- (oxiran-2-ylmethyl) piperazine-1-carboxylate, 4- [2- (2-methyloxyran-2-yl) ethyl] terbutyl piperazine-1-carboxylate or benzyl 4- (2-methyloxyran-2-ylmethyl) piperazine-1-carboxylate gave compounds of Examples 313 to 315 in the same manner as in Example 312.

Example 313

4- [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxypropyl] terp-butyl piperazine-1-carboxylate [2648] Light yellow powder, 43% yield [2649] ¹ H NMR ( CDCb) δ ppm:

[2650] 1.46 (9H, s), 2.16 - 2.50 (4H, m), 2.55 - 2.70 (2H, m), 3.40-3.51 (4H, m) ,

3.64 (1H, s), 3.91 -4.09 (2H, m), 4.17 (1H, dd, J = 2.0 Hz, 13.5 Hz), 8.00 (1H, s ). Example 314

4- [4- (2-chloro-4-nitroim idazol-1-yl) -3-hydroxy-3-methyl ethyl] piperazine-1-carboxylate

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643/854 [2651] White powder, 17% yield [2652] ¹ H NMR (CDCb) δ ppm:

[2653] 1.23 (3H, s), 1.40 - 1.74 (11H, m), 2.23 - 2.58 (5H, m), 2.81 - 2.95 (1H, m) ,

3.26 - 3.51 (4H, m), 3.91 (1H, d, J = 14.0 Hz), 3.99 (1H, d, J = 14.0 Hz), 6.94 (1H , s), 8.07 (1H, s).

Example 315

Benzyl 4- [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine -1 carboxylate [2654] Light yellow oil, 81% yield [2655] ¹ H NMR (CDCb) δ ppm:

[2656] 1.14 (3H, s), 2.35 - 2.76 (6H, m), 3.43 - 3.61 (4H, m), 4.01 (2H, s), 5.13 (2H,

s), 7.28 - 7.43 (5H, m), 8.04 (1H, s).

Example 316

Preparation of isobutyl 4- [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1 carboxylate [2657] A mixture of 1- [3- (4-ter -butoxycarbonylpiperazin-1-yl) -2-hydroxy-2methyl] propyl-2-chloro-4-nitroimidazole prepared in Example 312 (150 mg, 0.37 mmol) and trifluoroacetic acid (5 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml). Triethylamine (0.23 ml, 1.63 mmol) and isobutyl chloroformate (112 mg, 0.82 mmol) were added to the solution in that order, followed by stirring at room temperature for 30 minutes. The reaction mixture was washed with water, a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure giving isobutyl 4- [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy2-methylpropyl] piperazine-1-carboxylate, which was used in the next step without purification .

[2658] ¹ H NMR (CDCb) δ ppm:

[2659] 0.93 (6H, d, J = 6.7 Hz), 1.14 (3H, s), 1.82 -2.00 (1H, m), 2.39 (1H, d, J =

13.9 Hz), 2.47-2.73 (5H, m), 3.11 (1H, d, J = 7.3 Hz), 3.17 (1H, d, J = 7.3 Hz) , 3.41

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3.55 (4H, m), 3.87 (2H, s), 4.04 (1H, s), 8.10 (1H, s).

Example 317

Preparation of 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine

Benzyl 1-carboxylate [2660] To a mixture of benzyl 4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2methylpropyl] piperazine-1-carboxylate prepared in Example 315 (55 , 22 g, 126.11 mmol) and 1,4-dioxane (550 ml), sodium hydride (6.05 g, 151.25 mmol) was added, followed by stirring at reflux for 14 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride twice. The organic phases were washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate) giving 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1- b] benzyl oxazol-2-methyl) piperazine-1-carboxylate (26.54 g, 52% yield) as a white powder.

[2661] Melting point 130.5-132.1 ° C [2662] ¹ H NMR (CDCb) δ ppm:

[2663] 1.61 (3H, s), 2.38 - 2.69 (5H, m), 2.86 (1H, d, J = 14.8 Hz), 3.10 - 3.50 (4H ,

m), 3.92 (1H, d, J = 9.9 Hz), 4.33 (1H, d, J = 9.9 Hz), 5.11 (2H, s), 7.23 - 7, 38 (5H, m), 7.53 (1H, s).

[2664] Using corresponding starting materials, compounds of Examples 318 to 320 were obtained in the same manner as in Example 317.

Example 318

Isobutyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2665] Light yellow powder, 39% yield, melting 176.5-177.3 ° C. Example 319

Terbutyl 4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate

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645/854 [2666] White powder, 45% yield.

[2667] Melting point 185-188 ° C (decomposition) [2668] ¹ H NMR (CDCb) δ ppm:

[2669] 1.45 (9H, s), 2.48 - 2.58 (4H, m), 2.85 (2H, d, J = 5.1 Hz), 3.31 - 3.45 (4H ,

m), 4.20 (1H, dd, J = 6.9 Hz, 10.3 Hz), 4.34 (1H, dd, J = 8.4 Hz, 10.3 Hz), 5.35 - 5 , 48 (1H, m), 7.55 (1H, s).

Example 320

4- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl] piperazine-1-carboxylate ter-butyl [2670] Light yellow powder, 70% yield, melting point 190-191 ° C (decomposition).

Example 321

Preparation of tert-butyl 4- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2yl) propyl] piperazine-1-carboxylate [2671] A mixture of methanesulfonate 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl (2 g, 6.6 mmol), terbutyl piperazine-1-carboxylate (1.4 g, 7.5 mmol), triethylamine (1.3 g, 12.85 mmol), potassium iodide (1.8 g, 10.8 mmol) and DMF (15 ml) was stirred at 60 ° C for one day To the other. The reaction mixture was allowed to return to room temperature and then received the addition of water, and the resulting solution was extracted with ethyl acetate three times. The organic phases were combined, washing with water twice and then with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving 4 [3- (2-methyl-6-nitro-2, Ter-butyl 3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl] piperazine-1-carboxylate (1.9 g, 73% yield) as a white powder.

[2672] Melting point 166-167 ° C.

Example 322

Preparation of 2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride

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646/854 [2673] 2- (4-Ter-butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole prepared in Example 306 (1.19 g, 3.24 mmol) was dissolved in trifluoroacetic acid (30 ml), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml) and received a slow addition of a solution of hydrogen chloride in ethyl acetate, followed by stirring for 30 minutes with cooling in an ice bath. The precipitates were removed by filtration giving 2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1b] oxazole dihydrochloride (1.06 g, 96% yield) as a yellow powder.

[2674] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[2675] 1.68 (3H, s), 3.00 - 3.59 (6H, m), 4.14 (1H, d, J = 11.1 Hz), 4.36 (1H, d, J =

11.1 Hz), 4.50-6.12 (4H, br), 8.17 (1H, s), 9.62 (2H, br).

Example 323

Preparation of 2- [4- (biphenyl-4-ylmethyl) piperazin-1-ylmethyl] -6-nitro-2,3-dihydroimidazo [2,1 b] oxazole [2676] A mixture of 4- (6-nitro- 2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) piperazine-1-carboxylate ter-butyl prepared in Example 319 (400 mg, 1.13 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was dissolved in methylene chloride (10 ml) and neutralized with triethylamine (2 ml, 14.35 mmol). The resulting solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-phenylbenzaldehyde (515 mg, 2.83 mmol), sodium cyanotrihydroborate (214 mg, 3.41 mmol) and acetic acid (0.21 mg, 3.67 mmol) were added in this order, followed by stirring. at room temperature overnight. The reaction mixture was concentrated. Water was added to the residue, and the solution was extracted with methylene chloride twice. The organic phases were combined, washing with a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1)

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647/854 giving 2- [4- (biphenyl-4-ylmethyl) piperazin-1-ylmethyl] -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (188 mg, 40% yield) as a white powder.

[2677] Melting point 183-185 ° C (decomposition).

[2678] Using corresponding starting materials, compounds of Examples 324 to 329 were obtained in the same manner as in Example 323.

Example 324

2- {2- [4- (4-trifluoromethylbenzyl) piperazin-1-yl] ethyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazole [2679] White powder, yield 36 %, melting point 148-149 ° C.

Example 325

2-methyl-6-nitro-2- {3- [4- (4-trifluoromethylbenzyl) piperazin-1-yl] propyl} -2,3dihydroimidazo [2,1-b] oxazole [2680] White powder, yield 57 %.

[2681] Melting point 154-156 ° C.

Example 326

2- {2- [4- (Biphenyl-4-ylmethyl) piperazin-1-yl] ethyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1 b] oxazole [2682] White powder , 53% yield.

[2683] Melting point 181 -182 ° C.

Example 327

2- {3- [4- (Biphenyl-4-ylmethyl) piperazin-1-yl] propyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1 b] oxazole [2684] White powder , 65% yield.

[2685] Melting point 176-178 ° C.

Example 328

4- (N, N-dimethylamino) -4 '- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-ylmethyl] biphenyl [2686 ] White powder, 68% yield [2687] ¹ H NMR (CDCb) δ ppm:

[2688] 1.58 (3H, s), 2.36 (4H, br), 2.50 - 2.60 (2H, m), 2.54 (1H, d, J = 14.8 Hz),

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648/854

2.67-2.76 (2H, m), 2.84 (1H, d, J = 14.8 Hz), 2.99 (6H, s), 3.41 (1H, d, J = 12, 9 Hz),

3.48 (1H, d, J = 12.9 Hz), 3.87 (1H, d, J = 9.7 Hz), 4.30 (1H, d, J = 9.7 Hz), 6, 76 - 6.82 (2H, m), 7.25 - 7.29 (2H, m), 7.46 - 7.51 (4H, m), 7.53 (1H, s).

Example 329

2-methyl-6-nitro-2- [4- (2-phenyl-1 H-imidazol-4-ylmethyl) piperazin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole [2689] White powder , 93% yield [2690] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[2691] 1.52 (3H, s), 2.10-2.64 (6H, m), 2.67 (1H, d, J = 15.4 Hz), 2.74 (1H, d, J =

15.4 Hz), 3, 10 - 3.70 (4H, br), 4.04 (1H, d, J = 10.7 Hz), 4.21 (1H, d, J = 10.7 Hz) , 6.97 (1H, br), 7.27-7.34 (1H, m), 7.38-7.45 (2H, m), 7.88-7.93 (2H, m), 8 , 12 (1H, s). Example 330

Preparation of 2- (3,4-dichlorophenyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethyl) piperazin-1-yl] ethanone [ 2692] A mixture of 3,4- (dichlorophenyl) acetic acid (418 mg, 2.04 mmol) and thionyl chloride (3 ml) was stirred at reflux for 6 hours. The reaction mixture was concentrated under reduced pressure giving a corresponding acid chloride.

[2693] On the other hand, a mixture of 2- (4-ter-butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 306 (300 mg, 0.816 mmol) and trifluoroacetic acid (6 ml) was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml) and received the addition of triethylamine (2 ml,

14.35 mmol). A solution of the acid chloride obtained above in methylene chloride (5 ml) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 30 minutes. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, water and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 2 (3,4-dichlorophenyl) -1- [4- ( 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2

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649/854 ilmethyl) piperazin-1-yl] ethanone (255 mg, 69% yield) as a white powder. [2694] Melting point 189-191 ° C.

[2695] Using corresponding starting materials, compounds of Examples 331 and 332 were obtained in the same manner as in Example 330.

Example 331

1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -2- (4trifluoromethylphenyl) ethanone [2696] melting 168-171.4 ° C.

Example 332

2- (3,4-Dichlorophenoxy) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2- i Im ethyl) piperazin-1-yl ] ethanone [2697] Melting point 209-211 ° C.

Example 333

Preparation of 2- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin1-yl] -N- (4-trifluoromethylphenyl) acetamide [2698] A mixture of 2- (4-ter-butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 306 (500 mg, 1.36 mmol) and trifluoroacetic acid (15 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml) and received the addition of triethylamine (2 ml,

14.35 mmol). The solution was concentrated under reduced pressure, and the residue was dissolved in DMF (10 ml). 2-bromo-N- (4trifluoromethylphenyl) acetamide (423 mg, 1.5 mmol), potassium carbonate (207 mg, 1.5 mmol), and sodium iodide (204 mg, 1.36 mmol) were added to the solution ), followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 2- [4- (2-methyl-6-nitro-2 , 3-dihydroimidazo [2,1-b] oxazole-

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650/854

2-ylmethyl) piperazin-1-yl] -N- (4-trifluoromethylphenyl) acetamide (389 mg, 61% yield) as a white powder.

[2699] ¹ H NMR (CDCb) δ ppm:

[2700] 1.62 (3H, s), 2.53 - 2.84 (9H, m), 2.88 (1H, d, J = 14.8 Hz), 3.06 (1H, d, J =

16.7 Hz), 3.14 (1H, d, J = 16.7 Hz), 3.93 (1H, d, J = 9.7 Hz), 4.30 (1H, d, J = 9.7 Hz ), 7.55 (1H, s), 7.55 - 7.59 (2H, m), 7.65 - 7.71 (2H, m), 9.20 (1H, s).

[2701] Using corresponding starting materials, compounds of Examples 334 to 336 were obtained in the same manner as in Example 333.

Example 334 [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] ethyl acetate [2702] ¹ H NMR (CDCb) δ ppm:

[2703] 1.25 (3H, t, J = 7.1 Hz), 1.60 (3H, s), 2.45 - 2.64 (6H, m), 2.55 (1H, d, J =

14.8 Hz), 2.72-2.81 (2H, m), 2.87 (1H, d, J = 14.8 Hz), 3.14 (2H, s), 3.90 (1H, d, J = 9.7 Hz), 4.16 (2H, q, J = 7.1 Hz), 4.31 (1H, d, J = 9.7 Hz), 7.57 (1H, s).

Example 335

3- {3- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] propyl} 3H-benzoxazol-2-one [2704] Melting point 123-126 ° C.

Example 336

1- (4-chlorophenyl) -2- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin1-yl] ethanone [2705] ¹ H NMR (CDCb) δ ppm:

[2706] 1.60 (3H, s), 2.47 (4H, br), 2.53 (1H, d, J = 14.9 Hz), 2.57 - 2.65 (2H, m),

2.74 - 2.84 (2H, m), 2.87 (1H, d, J = 14.9 Hz), 3.64 (1H, d, J = 16.7 Hz), 3.75 (1H , d, J = 16.7 Hz), 3.90 (1H, d, J = 9.7 Hz), 4.30 (1H, d, J = 9.7 Hz), 7.42 (2H, d , J = 8.6 Hz), 7.54 (1H, s), 7.92 (2H, d, J = 8.6 Hz).

Example 337

Preparation of benzyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate

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651/854 [2707] A mixture of 2- (4-ter-butoxycarbonyl-piperazin-1-yl) methyl-2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 306 (130 mg, 0.35 mmol), trifluoroacetic acid (3 ml) and methylene chloride (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and received the addition of triethylamine (107.5 mg, 1.06 mmol). Benzyl chloroformate (120 mg, 0.71 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving a yellow oil. The oil was dissolved in ethyl acetate (5 ml). A saturated solution of hydrochloride in ethyl acetate was added to the solution, and the precipitates were removed by filtration giving 4 (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2- hydrochloride ylmethyl) benzyl piperazine-1-carboxylate (46.8 mg, 30% yield) as a white powder.

[2708] Melting point 130.5-132.1 ° C.

[2709] Using corresponding starting materials, compounds of Examples 338 to 340 were obtained in the same manner as in Example 337.

Example 338

Phenyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2710] Melting point 81-85 ° C.

Example 339

Isopropyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2711] Melting point 158.3-159.8 ° Ç.

Example 340

4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate noctila

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652/854 [2712] Melting point 138-139.4 ° C.

Example 341

Preparation of 4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate of 4-trifluoromethylbenzyl [2713] To the solution of 4- (6-nitro-2,3 -dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-tert-butylcarboxylate prepared in Example 319 (400 mg, 1.13 mmol) in methylene chloride (2 ml), trifluoroacetic acid ( 1 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (1 ml) and neutralized with triethylamine (1 ml).

[2714] A mixture of 4-trifluoromethylbenzyl alcohol (297 mg, 1.69 mmol), 1,1'-carbonyldiimidazole (274 mg, 1.69 mmol) and DMF (1 ml) stirred at temperature was added to the solution room for 1 hour, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate twice. The organic phases were combined, washing with water twice and then with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving 4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine 4-trifluoromethylbenzyl -1-carboxylate (322 mg, 63% yield) as a light yellow powder.

[2715] Melting point 120-122 ° C.

[2716] Using corresponding starting materials, compounds of Examples 342 and 343 were obtained in the same manner as in Example 341.

Example 342

4- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl] piperazine-1-carboxylate of 4-trifluoromethylbenzyl [2717] Light yellow powder, 68% yield, melting point 139-140 ° C. Example 343

4- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl] piperazine-1

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653/854 4-trifluoromethylbenzyl carboxylate [2718] Light yellow powder, 57% yield, melting point 130-133 ° C. Example 344

Preparation of 3- (4-trifluoromethylphenyl) -2-propynyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2719] A mixture of 2- (4-ter-butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 306 (220 mg, 0.6 mmol), trifluoroacetic acid (1 ml) and methylene chloride (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (2 ml) and neutralized with triethylamine (1 ml, 7.17 mmol). The resulting solution was concentrated under reduced pressure, and the residue was dissolved in DMF (2 ml).

[2720] A mixture of 3- (4-trifluoromethylphenyl) -2-propin-1ol (110 ml, 0.55 mmol), 1,1'-carbonyldiimidazole (90 mg, 0.55 mmol) and DMF (2 ml) stirred at room temperature for 2 hours, followed by stirring at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate twice. The organic phases were combined, washing with water twice and then with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 5/1).

[2721] The resulting free form was dissolved in ethanol (5 ml) and received the addition of a solution of maleic acid (96 mg, 0.83 mmol) in ethanol (5 ml). The precipitates were removed by filtration giving 3- (4-trifluoromethylphenyl) -2-propynyl 4 (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine maleate 1-carboxylate (227 mg, 68% yield) as a white powder.

[2722] Melting point 166 ° C (decomposition).

Example 345

Preparation of 4-methylsulfanylbenzyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate

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654/854 [2723] A mixture of 2- (4-ter-butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 306 (900 mg, 2.4 mmol) and trifluoroacetic acid (20 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (20 ml) and neutralized with triethylamine (6 ml, 43.05 mmol). The resulting mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (5 ml).

[2724] A mixture of 4-methylsulfanylbenzyl alcohol (470 mg, 3 mmol), 1,1'-carbonyldiimidazole (500 mg, 3.1 mmol) and DMF (10 ml) stirred at room temperature was added to the solution 3 hours, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washing with water twice, and then with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole -2-methyl) piperazine-1-carboxylate of 4-methylsulfanylbenzyl (860 mg, 79% yield) as a white powder.

[2725] Melting point 118-120 ° C.

Example 346

Preparation of 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate 4-methanesulfinylbenzyl [2726] To a mixture of 4- (2- 4-methylsulfanylbenzyl methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl-1-carboxylate prepared in Example 345 (300 mg, 0.67 mmol) and sodium chloride was added methylene (10 ml), chloroperbenzoic acid (210 mg, 0.85 mmol), followed by stirring for 2 hours with cooling in an ice bath. The reaction mixture was washed with a saturated sodium sulfite solution, a saturated sodium hydrogen carbonate solution, and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized

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655/854 isopropyl ether alcohol giving 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate 4-methanesulfinylbenzyl (203 mg, 65% yield) as a white powder.

[2727] Melting point 117-121 ° C.

Example 347

Preparation of 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate 4-hydroxybenzyl [2728] To a mixture of 4- (2- 4- (tert-butyldimethylsilanyloxy) benzyl (400 mg, 0.75 mmol) and THF (10 ml) methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) ), a 1M solution of tetrabutylammonium fluoride in THF (0.8 ml, 0.8 mmol) was added, followed by stirring for 20 minutes with cooling in an ice bath. To the reaction mixture, ethyl acetate was added, and the solution was washed with a saturated solution of ammonium chloride, water and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitates were removed by filtration giving 4- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate of 4-hydroxybenzyl (95 mg, 30% yield) as a light yellow powder.

[2729] ¹ H NMR (CDCb) δ ppm:

[2730] 1.59 (3H, s), 2.30 - 2.70 (4H, m), 2.56 (1H, d, J = 15.0 Hz), 2.86 (1H, d, J =

15.0 Hz), 3.10-3.55 (4H, m), 3.91 (1H, d, J = 10.0 Hz), 4.28 (1H, d, J = 10.0 Hz) , 5.03 (2H, s), 5.30 (1H, brs), 6.84 (2H, d, J = 8.0 Hz), 7.24 (2H, d, J = 8.0 Hz) , 7.53 (1H, s). Example 348

Preparation of 4-acetylbenzyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2731] A mixture of 4- (2-methyl -6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate 4- (1,1-dimethoxyethyl) benzyl (600 mg, 1.23 mmol), hydrochloric acid 1 N (10 ml, 10 mmol) and THF (15 ml) was stirred at room temperature for 2 hours, then neutralized with a saturated solution of sodium hydrogen carbonate, and the resulting mixture was extracted with ethyl acetate.

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656/854

The organic phase was washed with water and then with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitates were removed by filtration giving 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate 4-acetylbenzyl (558 mg, 99% yield) as a white powder.

[2732] Melting point 101 -102 ° C.

Example 349

Preparation of 4-benzoylbenzyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine1-carboxylate [2733] Using 4- (2-methyl-6 -nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate 4- [dimethoxy (phenyl) methyl] benzyl (800 mg, 1.45 mmol) 4- ( 4-benzoyl benzyl 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate (630 mg, 86% yield) as a white powder in the same way as in Example 348.

[2734] Melting point 105-107 ° C.

Example 350

Preparation of 4-aminobenzyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2735] A mixture of 4- (2-methyl -6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate 4- (ter-butoxycarbonylamino) benzyl (340 mg, 0.66 mmol), trifluoroacetic acid (2 ml ) and methylene chloride (10 ml) was stirred at room temperature for 2 hours, and then neutralized with a saturated sodium hydrogen carbonate solution. The organic phase was washed with water and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitates were removed by filtration giving 4- (2-methyl-6-nitro-

4-Aminobenzyl 2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate (100 mg, 37% yield) as a light yellow powder.

[2736] ¹ H NMR (CDCb) δ ppm:

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657/854 [2737] 1.61 (3H, s), 2.35-2.70 (4H, m), 2.56 (1H, d, J = 15.0 Hz), 2.85 (1H, d, J =

15.0 Hz), 3.05-3.55 (4H, m), 3.69 (2H, brs), 3.91 (1H, d, J = 10.0 Hz), 4.28 (1H, d, J = 10.0 Hz), 4.98 (2H, s), 6.55 (2H, d, J = 8.0 Hz), 7.14 (2H, d, J = 8.0 Hz) , 7.53 (1H, s).

Example 351

Preparation of 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylic acid hydrochloride [2738] A mixture of 2- (4- ter-butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 306 (130 mg, 0.35 mmol) and trifluoroacetic acid (3 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (3 ml), then neutralized with triethylamine (2 ml, 14.35 mmol). Phenylisocyanate (63 mg, 0.53 mmol) was added to the solution, followed by stirring at room temperature for 30 minutes, and then diluted with water. The solution was extracted with methylene chloride, and the organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving an amorphous form.

[2739] The amorphous form was dissolved in ethyl acetate. A saturated solution of hydrochloric acid in ethyl acetate was added to the solution, and the resulting precipitates were removed by filtration giving 4 (2-methyl-6-nitro-2,3-dihydroimidazo) phenylamide hydrochloride [2,1- b] oxazol-2-ylmethyl) piperazine-1-carboxylic (124 mg, 55% yield) as a light yellow powder.

[2740] ¹ H NMR (DMSO-de) δ ppm:

[2741] 1.55 (3H, s), 2.50 - 2.56 (4H, m), 2.75 (2H, s), 3.21 - 3.40 (4H, m), 4.05 (1H, d, J = 10.7 Hz), 4.24 (1H, d, J = 10.7 Hz), 6.92 -6.99 (1H, m), 7.21 -7.28 ( 2H, m), 7.44 -7.48 (2H, m), 8.13 (1H, s), 8.59 (1H, s).

Example 352

Preparation of 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazine-1-carboxylic acid isopropylamide

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658/854 [2742] A mixture of tert-butyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate prepared in Example 306 ( 140 mg, 0.38 mmol) and trifluoroacetic acid (3 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (3 ml), then neutralized with triethylamine (2 ml,

14.35 mmol). Isopropylisocyanate (75 μΙ, 0.76 mmol) was added to the solution, followed by stirring at room temperature for 1 hour, then diluted with water. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving 4- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] isopropylamide oxazol-2-ylmethyl) piperazine-1-carboxylic (90 mg, 67% yield) as a white powder.

[2743] Melting point 175-176.3 ° C.

[2744] Using corresponding starting materials, compounds of Examples 353 and 354 were obtained in the same manner as in Example 352.

Example 353 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (3-chlorophenyl) [2745] ¹ H NMR (DMSO -de) δ ppm:

[2746] 1.56 (3H, s), 2.50 - 2.56 (4H, m), 2.77 (2H, s), 3.21 - 3.40 (4H, m), 4.08 (1H, d, J = 10.7 Hz), 4.26 (1H, d, J = 10.7 Hz), 6.95 (1H, bd, J = 8.0 Hz), 7.23 (1H , t, J = 8.0 Hz), 7.36 (1H, bd, J = 8.0 Hz), 7.61 (1H, t, J = 2.0 Hz), 8.13 (1H, s ), 8.61 (1H, s). Example 354 4- (2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid cyclohexylamide [2747] Melting point 216.5-218 , 5 ° C.

Example 355

Preparation of 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazine-1-carbothioic (4-chlorophenyl) amide

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659/854 [2748] 2-Methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1b] oxazole dihydrochloride prepared in Example 322 (196 mg, 0.73 mmol) it was suspended in methylene chloride (10 ml), then neutralized with triethylamine (0.27 ml, 1.94 mmol). 4-Chlorophenyl isothiaocyanate (140 mg, 0.83 mmol) was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 30/1) giving 4- (2-methyl-6-nitro-2,3-dihydroimidazo) (4-chlorophenyl) amide [2,1-b] oxazol-2-ylmethyl) piperazine-1 carbobiotic (128 mg, 40% yield) as a light brown powder.

[2749] Melting point 204-206 ° C (decomposition).

[2750] Using corresponding starting materials, compounds of Examples 356 and 357 were obtained in the same manner as in Example 355.

Example 356 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carbothioic acid phenylamide [2751] Melting point 164-165 ° C (decomposition ).

Example 357 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carbothioic acid (4-methoxyphenyl) [2752] Melting point 189- 191 ° C (decomposition).

Example 358

Preparation of 2- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin1-yl] benzoxazole [2753] 2- (4-ter-Butoxycarbonylpiperazin -1-yl) methyl-2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole prepared in Example 306 (500 mg, 1.36 mmol) was dissolved in trifluoroacetic acid (10 ml), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and received the addition of methylene chloride (1 ml) and triethylamine (1 ml). The solution was

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660/854 stirred at room temperature for 5 minutes, and then concentrated under reduced pressure. The residue was dissolved in methylene chloride. 2-chlorobenzoxazole (0.19 ml, 1.63 mmol) and triethylamine (0.23 ml, 1.63 mmol) were added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from methylene chloride-diisopropyl ether giving 2- [4- (2-methyl-6-nitro-

2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] benzoxazole (325 mg, 62% yield) as a white powder.

[2754] MS 384 (M ⁺ ) [2755] Melting point 228.0-229.5 ° C.

[2756] Using corresponding starting materials, compounds of Examples 359 to 361 were obtained in the same manner as in Example 358.

Example 359 2- [4- (6-Nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] benzoxazole [2757] White powder, 74% yield [2758] MS 370 (M ⁺ ) [2759] Melting point 206-209 ° C (decomposition).

Example 360 2- {4- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl] piperazin-1yl} benzoxazol [2760] White powder, 73% yield [2761] MS 398 (M ⁺ ) [2762] Melting point 187.6-189.6 ° C.

Example 361 2- {4- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl] piperazin-1yl} benzoxazol [2763] White powder, 90% yield

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661/854 [2764] MS 412 (M ⁺ ) [2765] Melting point 172.0-174.4 ° C.

Example 362

Preparation of ter-butyl (S) -4- [3- (2-chloro-4-nitroim-idazol-1-yl) -2-hydroxypropyl] piperazine-1 carboxylate [2766] (R) -2-chlorine -1 - [2-hydroxy-3- (4-methylbenzenesulfonyloxy) propyl] -4nitroimidazole prepared in Example 8 (16.86 g, 44.86 mmol) and ter-butyl piperazine-1carboxylate (8.36 g, 44 , 89 mmol) were dissolved in acetonitrile (100 ml). Triethylamine (6.3 ml, 45.2 mmol) was added to the solution, followed by stirring at reflux for 6 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. Water (100 ml) was added to the residue and this was extracted with ethyl acetate (100 ml) twice. The organic phases were combined, washing with water (100 ml) and a saturated saline solution (100 ml) in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 40/1) and then recrystallized from ethyl acetate / n-hexane giving (S) - Tert-Butyl 4- [3- (2-chloro-4-nitroimidazol-1)) -2-hydroxypropyl] piperazine-1-carboxylate (11.61 g, 66% yield) as a light yellow powder.

[2767] ¹ H NMR (CDCb) δ ppm:

[2768] 1.46 (9H, s), 2.21 - 2.50 (4H, m), 2.54 - 2.70 (2H, m), 3.39 - 3.48 (4H, m) ,

3.65 (1H, s), 3.89-4.10 (2H, m), 4.20 (1H, dd, J = 1.9 Hz, 13.5 Hz), 8.00 (1H, s ). Example 363

Preparation of ter-butyl (S) -4- [3- (2-chloro-4-nitroim-idazol-1-yl) -2-hydroxypropyl] piperazine-1 carboxylate (alternative synthesis of the compound of Example 362) [ 2769] A mixture of (R) -2-chloro-1- (oxiran-2-ylmethyl) -4-nitroimidazole prepared in Example 9 (1 g, 4.91 mmol), tert-butyl piperazine-1-carboxylate ( 1.01 g, 5.40 mmol) and DMF (3 ml) was stirred at 70 ° C for 6 hours. The reaction mixture was allowed to return to room temperature and received the addition of water (7 ml). The precipitates were removed by filtration, and purified by means of

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662/854 column on silica gel (methylene chloride / methanol = 40/1) giving (S) -4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxypropyl] piperazine-1-carboxylate tert-butyl (967 mg, 51%) as a light yellow powder.

Example 364

Preparation of ter-butyl (R) -4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxypropyl] piperazine-1 carboxylate [2770] A mixture of 2-chloro- 4-nitro-1 H-imidazole (6.1 g, 41.35 mmol), (S) - (+) - glycidyl tosylate (12.27 g, 53.75 mmol) and sodium hydrogen carbonate (7.3 g, 86.89 mmol) in ethanol (30 ml) was stirred at reflux for 9 hours. The reaction mixture was allowed to return to room temperature, then diluted with water, and the solution was extracted with methylene chloride twice. The extract was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated to a foam. The resulting foam was dissolved in DMF (60 ml). To the solution tert-butyl piperazine-1-carboxylate (8.47 g, 45.48 mmol), triethylamine (6.92 ml, 49.64 mmol) and sodium iodide (6.82 g, 45, 5 mmol), followed by stirring at room temperature for 24 hours. The reaction mixture was poured into water, and extracted with ethyl acetate twice. The organic phases were combined, washing with water three times, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel (ethyl acetate) giving (R) -4- [3- (2-chloro-4-nitroimidazol-1-i) -2-hydroxypropyl 1] ter-butyl piperazine-1-carboxylate (6.43 g, 40% yield) as a light yellow oil.

[2771] ¹ H NMR (CDCb) δ ppm:

[2772] 1.48 (9H, s), 2.16 - 2.50 (4H, m), 2.55 - 2.69 (2H, m), 3.37 - 3.50 (4H, m) ,

3.65 (1H, s), 3.90 - 4.25 (3H, m), 8.00 (1H, s).

Example 365

Preparation of ter-butyl (S) -4- [3- (2-chloro-4-nitroim-idazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1-carboxylate [2773] A mixture of (R ) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (7.00 g, 32.2 mmol) and tert-butyl piperazine-1-carboxylate

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663/854 (6.29 g, 33.8 mmol) and DMF (70 ml) was stirred at 70 ° C for 8 hours. The reaction mixture was allowed to return to room temperature, then diluted with water, and then the solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water three times, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue. The precipitates were removed by filtration, and dried at room temperature under reduced pressure giving (S) -4- [3- (2-chloro-4-nitroimidazol1 -yl) -2-hydroxy-2-methylpropyl] piperazine-1-carboxylate tert-butyl (10.25 g, 79% yield) as a light yellow powder.

[2774] Optical purity> 98.4% e.e.

[2775] [a] d ²⁷ = 25.488 (concentration: 1.024, CHCb) [2776] ¹ H NMR (CDCb) δ ppm:

[2777] 1.14 (3H, s), 1.46 (9H, s), 2.34 (1H, d, J = 13.9 Hz), 2.47 - 2.67 (5H, m),

3.26 (1H, s), 3.44 (4H, t, J = 4.4 Hz), 3.99 (2H, s), 8.04 (1H, s).

Example 366

Preparation of ter-butyl (S) -4- [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1-carboxylate (alternative synthesis of the compound of Example 365) [2778] To the solution of 2-chloro-4-nitro-1 H-imidazole (89.4 g, 606 mmol) and (S) -4- (2-methyloxyran-2-ylmethyl) piperazine-1-carboxylate (119 g, 466 mmol) in ethanol (475 ml), sodium hydrogen carbonate (58.7 g, 699 mmol) was added, followed by stirring at reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added water. The mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was dispersed in ethyl acetate, and removed by filtration giving a solid. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (n-hexane / acetone = 3/1) giving a solid. The solids were combined and dried under reduced pressure giving (S) -4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1 carboxylate ter -butyl (84.7 g, 45% yield) as a white powder.

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Example 367

Preparation of (R) -4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1-carboxylate [2779] A mixture of (S) -2-chlorine -1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 18 (440 mg, 2.02 mmol), ter-butyl piperazine-1-carboxylate (414 mg, 2.22 mmol) and DMF (4 ml) was stirred at 55-60 ° C for 9 hours. The reaction mixture was allowed to return to room temperature, then diluted with water (24 ml), and the solution was extracted with ethyl acetate (10 ml) twice. The organic phases were combined, washing with water (20 ml) three times and a saturated saline solution (10 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether giving (R) -4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine -1-ter-butyl carboxylate (662 mg, 81% yield) as a light yellow powder.

[2780] ¹ H NMR (CDCb) δ ppm:

[2781] 1.15 (3H, s), 1.45 (9H, s), 2.34 (1H, d, J = 13.9 Hz), 2.48 - 2.67 (5H, m),

3.27 (1H, s), 3.44 (4H, t, J = 4.4 Hz), 3.99 (2H, s), 8.04 (1H, s).

[2782] Using 2-chloro-4-nitro-1 H-imidazole and ter-butyl (R) -4- (2-methyloxyran-2ylmethyl) piperazine-1-carboxylate the compound of Example 368 was obtained in the same way as in Example 366.

Example 368 (R) -4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1-carboxylate (alternative synthesis of the compound of Example 367 ) [2783] White powder, 20% yield.

Example 369

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethoxyphenyl) piperazin-1-yl] propan-2-ol [2784] A a suspension of (S) -1- (2-methyloxyran-2-ylmethyl) -4- (4trifluoromethoxyphenyl) piperazine (0.43 g, 1.37 mmol) and 2-chloro-4-nitro-1 H-imidazole ( 0.22 g, 1.51 mmol) in acetonitrile (4 ml), sodium hydrogen carbonate (0.17 g, 2.06 mmol) was added, followed by stirring at reflux for 9 hours. Water was added to the

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665/854 reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 3/1) giving (S) -1- (2-chloro-4-nitroimidazol-1-yl) -2- methyl-3- [4- (4trifluoromethoxyphenyl) piperazin-1-yl] propan-2-ol (0.20 g, 31% yield) as a light yellow oil.

[2785] ¹ H NMR (CDCb) δ ppm:

[2786] 1.18 (3H, s), 2.41 (1H, d, J = 13.8 Hz), 2.56 (1H, d, J = 13.8 Hz), 2.67-2, 80 (2H, m), 2.85-2.96 (2H, m), 3.13-3.25 (4H, m), 4.03 (2H, s), 6.83-6.93 ( 2H, m), 7.07 -7.17 (2H, m), 8.07 (1H, s).

Example 370

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4-chlorophenyl) piperazin1 -yl] propan-2-ol [2787] (R ) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in

Example 12 (20 g, 91.9 mmol) and 1- (4-chlorophenyl) piperazine (20.8 g, 0.11 mol) were added to DMF (200 ml), followed by stirring at 70-75 ° C for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving (S) -1- (2-chloro-4-nitroimidazole-1-yl) -2-methyl -3- [4- (4-chlorophenyl) piperazin-1-yl] propan-2-ol (33.0 g, 87% yield) as a yellow amorphous form.

[2788] ¹ H NMR (CDCb) δ ppm:

[2789] 1.53 (3H, s), 2.42 (1H, d, J = 13.9 Hz), 2.55 (1H, d, J = 13.9 Hz), 2.67-2, 76 (2H, m), 2.81 - 2.90 (2H, m), 3.13 - 3.17 (4H, m), 3.43 (1H, s), 4.03 (2H, s) , 6.78 - 6.85 (2H, m), 7.16-7.23 (2H, m), 8.06 (1H, s).

[2790] Using corresponding starting materials, compounds of Examples 371 to 384 shown in the following table were obtained, in the same manner as in Example 370.

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Table 17

Example R Rend. (¾) ^T H NMR (CDC1,) Λ 371 4-CFj 82 1.18Ϊ3Η. a), 2.4 ± 1H, d, J = 13.9HzX 2. & 6OH, d. J = 13.9Hi), 2.68 * 2.79 (2H, m), 2.62-2.91 (2H. M), 3.263.31Í3H, «), 4.03ÜH, s), 6.91 (2H, d, J = 8.7Hz), 7.49 Ϊ2Η, d. J-É.VHz), 8.06 (1 H. s). 372 4H 92 1.17I3H, i), 2.40I1H. d, J = 13.9 Hz). 2.55Í1H. d, J = 13.9Hz), 2.69-2.78 (2H, m), 2.83 * 2.91 (2H, m), 3.183.22 <4H, mi, 3.42I1H, s), 4.01 (211, e), 6.35 -6.93 (311, m), 7.24-7.31 (2H. M), 8.06 (1H. Ã). 373 4F 43 1.16Ϊ3Η, e). 2.41 (1H, d, J = 13.9Hzj, 2.5SÍ1H, 3, J = 13.9Hi}, 2.69-2.77Í2H, π). 2.82-2.91 (2H, m), 3.10 * 3.14 (411.m), 3.41 (1H, s), 4.01 (2H, s), 6.88-7.0M4H, m>. 8.06 (lH, sX 374 4-OMe 99 1.I5Í3H, s), 2.42 (1 H, d, J-LS.SHzj, 2.56 (111, d, J-13.9H =), 2.69-2.78Í2H, m), 2.S2-2.9K2H, m), 3.073.11Ϊ4Ή. mX 3.77 (311, s), 4.02H2H, and 6.81-6.91 (4H, m), 8.07C1H, â). 376 4-CODEt 100 1.17 (3Ή, U, 1.37 (3H, t, J = 7.1Hi}, 2.42Í1H, d, J = 13.9Hz), 2.56Í1H. D, J = 13.9Ha), 2.68 * 2.76 (2H , mX 2.81-2.89Í2H, m), 3.31 · 3.35 (4Η, m), 3.40 (IH, e), 4.04 (2H, e), 4.S3 (2H, q, J = 7.1Hz), 6.83-6.87 (211, m), 7.90-7.95 (2H, m), 8.06 (1H, s). 376 4-Me 86 l.I5 (3H, s), 2.27Í3H, s), 2.41ÜH, d, J = 13.9HzX 2.5õ (lH _r d, J = I3.9Hz), 2.68 2.77Ϊ2Η, m), 2.82 * 2.90 (211 , mX 3.12-a.l6 (4H, S.47 (1H, s), 4.01 (2H, a), 6.81-6.86 (2H. m}, 7.0fi-7.09 (2H. mX 8.06 (lH, s). 377 4 * UN 99 1.18 (311, a), 2.43I1H, d, J = I3.ÔHz), 2.66 (111, d, J = 13.9HzX 2.66-2.75 (2H, mi, 2.fll-2.90 (2H, mX 3,313.35 ( 4H, m), 3.6ΙΪ1Η, s), 4.03 (lH, d, J = 14.3Hzí, 4.09Í1H, d, J-14.3Hz), 6.82-6.8S (2H, m), 7.46-7.52Ϊ2Η, m) , S.D7 (1H, a). 378 3,4-diCl 99 1.17Í3H, a), 2.41ÍIH, d, J = 13.9Hz), 2.5G (1H, d, J = 13.9Bz), 2.68-2.76 (2H, m), 2.80 * 2.89 (211, m), 8,153.19 (4H, m), 3.40I1H, s), 4.03 (2H. S). 6.72 (1H, dd, J = 8.9, 2.9Hz), 6.94 (1H, d, J = 2.9Hz (7.28 (1H, d, J = 8.9Hz), 8.05 (1H, s). 375 3 * CF, 99 1.17Í3H, a), 2.42UH, d, J = 13.9Hz), 2.56 (1H, d, J- 13.9Hz), 2.69-2.7ΒΪ2Η, m), 2.83 * 2.93 (211, m), 3.223.27 (4H, m), 3.36 (1H, 'X 4.03 (2H, e), 7.03 * 7.11 (3H , m). 7.32 · 7.39 (1Η. mX 8.06C1H, s).

Table 17 (Continued)

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667/854

380 2-CFs BS 1.1GÍ3H, s), 2.44UH, d, J = 14.0Hz), 2.57 (1H, d, J-14.0Hz), 2.67-2.78Í2H, m), 2.Θ1-2.9Κ2Η, m), 2,932.96Í4H, m), 3.81 (1H, s), 4.05 (2H, b), 7.21-7.27 (1H, m). 7.35-7.39 (111, m), 7.50-7.57Ϊ1Η, pi). 7.60-7.64 (1H, m), & .11 (1H, b). 381 4-C1-3-CF, 99 1.1S (3H, s), 2.42 (1H, d, J-13.9Hz), 2.56 (1 «, d, J = 13.9Hi), 2.68-2.77Í2H, m), 2.83-2.92Í2H, m) , 3.19 · 3.24I4H, in). 3.40Í1H, a), 4.04Í2H, e), 6.95Ϊ1Η, dd, J = 8.9, 2.9Hs). 7.160H, d, J = 2.9Hz), 7.34 (1H, d, J = 8.9Hz), 8O6 (1H, b). 382 4-COO’Bu 99 1.17Í3H, s), 1.57 (911. S), 2.42ÜE, d, J = 13.9Hz), 2.65Í1H, d, J = 13.9 «2). 2.67-2.76 (SE, iu), 2.81-2.90 (2 «, m), 3,293.33Í4H, m), 3.51ÚH, í), 4.C4Í2H, s), 6.64Ϊ2Η, d, <U9.0Hz), 7.87 (2H, d. J ~ 9.0Hz), 8.α7 (1Η, s). 383 2-F 99 1.16 (3H _h (1), 2.42 (lH..d, J-13.9Hz), 2.57 (1 «, d, <1 = 13.9Hz), 2.71-2.8ΟΪ2Η, m). 2.85-2 / 96 (211. M), 3,103.14 (4), m), 3.56 (1), s). 4.02 ± 2H, s), 6.91-7.10 (4E, m), 8.07 ± 1H, a). 384 4-NMe, 82 1.14 (311, a), 2.4Ú (1H, d, J ^ 13.9Hz), 2.54 (1H, d, J-13.9Hz), 2.70-2.77 (211, m), 2.81-2.91 (611, m), 3.0 & 3.09 (4H, m), 3.8β (1Η, a), 4.0K2H, b), 6.72-6.76 (2H, m), 6-66-6.91 (2H. M), 3.07 (lH, i).

[2791] Using corresponding starting materials, compounds of Examples 385 and 386 were obtained in the same manner as in Example 370.

Example 385 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4-pyridyl) piperazin-1-yl] propan-2-ol [2792] 100% yield [2793] ¹ H NMR (CDCb) δ ppm:

[2794] 1.18 (3H, s), 2.44 (1H, d, J = 13.9 Hz), 2.56 (1H, d, J = 13.9 Hz), 2.63-2, 73 (2H, m), 2.77 - 2.91 (2H, m), 3.31 - 3.35 (4H, m), 3.54 (1H, s), 4.03 - 4.12 ( 2H, m), 6.63 - 6.66 (2H, m), 8.09 (1H, s), 8.23 - 8.27 (2H, m).

Example 386 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (3-pyridyl) piperazin-1-yl] propan-2-ol [2795] 81% yield [2796] ¹ H NMR (CDCb) δ ppm:

[2797] 1.17 (3H, s), 2.44 (1H, d, J = 13.9 Hz), 2.57 (1H, d, J = 13.9 Hz), 2.67-2, 79 (2H, m), 2.84 - 2.93 (2H, m), 3.20 - 3.25 (4H, m), 3.85 (1H, bs), 4.06 (2H, s) , 7.16 7.19 (2H, m), 8.07-8.11 (2H, m), 8.26 - 8.28 (1H, m).

[2798] Using (R) -2-chloro-4-nitro-1- (oxiran-2-ylmethyl) imidazole prepared in Example 9, compounds of Examples 387 to 389 were obtained in the same manner as in Example 370.

Example 387

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668/854 (S) -1 - (2-chloro-4-nitroimidazole-1-yl) -3- [4- (4-fluoropheni) piperazin-1-yl] propan-2-ol [2799] yield of 86 % [2800] ¹ H NMR (CDCb) δ ppm:

[2801] 2.27-2.36 (1H, m), 2.49 - 2.63 (3H, m), 2.78-2.88 (2H, m), 2.97 - 3.18 ( 4H,

m), 3.74 (1H, br), 3.96 - 4.08 (2H, m), 4.18 - 4.24 (1H, m), 6.84 - 7.01 (4H, m) , 8.02 (1H, s).

Example 388 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3- [4- (4-trifluoromethylphenyl) piperazin-1 -yl] propan-2-ol [2802] 49% yield [2803] ¹ H NMR (CDCb) δ ppm:

[2804] 2.27 - 2.36 (1H, m), 2.49 - 2.63 (3H, m), 2.78 - 2.87 (2H, m), 3.28 - 3.31 ( 4H,

m), 3.62 (1H, br), 3.95 - 4.11 (2H, m), 4.19 - 4.25 (1H, m), 6.92 (2H, d, J = 8, 6 Hz),

7.49 (2H, d, J = 8.6 Hz), 8.02 (1H, s).

Example 389 (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3- [4- (4-cyanophenyl) piperazin-1-yl] propan-2-ol [2805] 100% yield [2806] ¹ H NMR (CDCb) δ ppm:

[2807] 2.28 - 2.37 (1H, m), 2.49 - 2.63 (3H, m), 2.76 - 2.85 (2H, m), 3.28 - 3.36 ( 4H,

m), 3.58 (1H, br), 3.96 - 4.12 (2H, m), 4.19 - 4.25 (1H, m), 6.87 (2H, d, J = 8, 9 Hz),

7.51 (2H, d, J = 8.9 Hz), 8.01 (1H, s).

Example 390

Preparation of 4-trifluoromethoxybenzyl (S) -4- [3- (2-chloro-4-nitroim-idazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1-carboxylate [2808] A mixture of (R ) Benzyl -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (15 g, 68.93 mmol) and benzyl 4-trifluoromethoxypiperazine-1carboxylate (25.17 g, 82 , 72 mmol) in DMF (75 ml) was stirred at 65-70 ° C for 20 hours. The reaction mixture was allowed to return to room temperature and poured into water (475 ml), and extracted with ethyl acetate (150 ml). The aqueous layer was again extracted with ethyl acetate (150 ml). The organic phases were combined, washing with water (400 ml) 3 times and saline

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669/854 saturated (100 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / n-hexane = 1/2) giving (S) -4- [3- (2-chloro-4-nitroim idazol-1-yl) - 4-trifluoromethoxybenzyl 2-hydroxy-2-methylpropyl] piperazine-1-carboxylate (29.98 g, 83% yield) as a yellow oil.

[2809] ¹ H NMR (CDCb) δ ppm:

[2810] 1.15 (3H, s), 2.36 (1H, d, J = 14.0 Hz), 2.42 - 2.75 (5H, m), 3.18 (1H, s),

3.42 - 3.58 (4H, m), 4.00 (2H, s), 5.12 (2H, s), 7.21 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz), 8.03 (1H, s).

Example 391

Preparation of 3- (4-trifluoromethylphenyl) -2-propenyl (S) -4- [3- (2-chloro-4-nitroim idazol-1 -yl) -2-hydroxy-2-methylpropyl] piperazine-1-carboxylate [2811] A mixture of (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (4.24 g, 19.48 mmol) and piperazine-1-carboxylate 3- (4trifluoromethylphenyl) -2-propenyl (6.73 g, 21.41 mmol) in DMF (21 ml) was stirred at 5055 ° C for 24 hours. The reaction mixture was allowed to return to room temperature and poured into water (90 ml), and extracted with ethyl acetate (60 ml). The aqueous layer was again extracted with ethyl acetate (60 ml). The organic phases were combined, washing with water (90 ml) 3 times and a saturated saline solution (60 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / n-hexane = 1/1) giving (S) -4 [3- (2-chloro- 3 (4-trifluoromethylphenyl) -2-propenyl 4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] -2-propenyl (9.29 g, 90% yield) as a yellow oil. [2812] ¹ H NMR (CDCb) δ ppm:

[2813] 1.16 (3H, s), 2.36 (1H, d, J = 14.0 Hz), 2.43 - 2.76 (5H, m), 3.17 (1H, s),

3.48 - 3.67 (4H, m), 4.00 (2H, s), 4.78 (2H, dd, J = 1.0 Hz, 6.1 Hz), 6.33 - 6.48 (1H, m),

6.66 (1H, d, J = 15.9 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.58 (2H, d, J = 8.3 Hz), 8, 04 (1H, s).

[2814] Using the corresponding starting materials, the compound of

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Example 392 in the same way as in Example 391.

Example 392 (3- (2-chlorofluoromethoxyphenyl) -2-propenyl) 3- (4-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1-carboxylate [2815] ¹ H NMR (CDCb) δ ppm:

[2816] 1.15 (3H, s), 2.36 (1H, d, J = 13.9 Hz), 2.51 (1H, d, J = 13.9 Hz), 2.48-2, 63 (2H, m), 2.63-2.78 (2H, m), 3.17 (1H, s), 3.39-3.63 (4H, m), 4.00 (2H, s) , 4.75 (2H, dd, J = 1.1 Hz, 6.3 Hz), 6.28 (1H, dt, J = 6.3 Hz, 15.9 Hz), 6.62 (1H, d , J = 15.9 Hz), 7.15 - 7.18 (2H, m), 7.38 - 7.42 (2H, m), 8.03 (1H, s).

Example 393

Preparation of ter-butyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate [2817] (S) -4 - Ter-butyl [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1carboxylate prepared in Example 365 (10.25 g, 25.4 mmol) was dissolved in DMF (30 ml). Sodium hydride (1.12 g, 27.9 mmol) was added to the solution, followed by stirring for 2 hours with cooling in an ice bath. Ethyl acetate (10 ml) and water (70 ml) were added to the reaction mixture. The precipitates were removed by filtration, and washed with water. The crude solids were recrystallized from ethyl acetate (70 ml) giving (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethyl) piperazine-1-carboxylate tert-butyl (6.62 g, 71% yield) as a light yellow powder.

[2818] Optical purity> 99.5% e.e.

[2819] [oc] d ²⁷ = -20.953 ° (concentration: 0.492, CHCb) [2820] ¹ H NMR (CDCb) δ ppm:

[2821] 1.44 (9H, s), 1.62 (3H, s), 2.45 - 2.66 (5H, m), 2.87 (1H, d, J = 14.9 Hz),

3.29 (4H, br), 3.92 (1H, d, J = 9.7 Hz), 4.30 (1H, d, J = 9.7 Hz), 7.53 (1H, s).

Example 394

Preparation of ter-butyl (S) -4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2822] Using (S) -4- [3 - (2-chloro-4-nitroimidazol-1-yl) -2-hydroxypropyl] piperazine

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671/854

Tert-butyl 1-carboxylate prepared in Example 363 (11 g, 28.22 mmol) (S) -4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2- terbutyl ylmethyl) piperazine-1-carboxylate (7.5 g, 75% yield) as a light yellow powder in the same manner as in Example 393.

[2823] Optical purity 96.6% e.e.

[2824] [a] d ²² = -11.91 ° (concentration: 1.016, CHCb) [2825] ¹ H NMR (CDCb) δ ppm:

[2826] 1.45 (9H, s), 2.49 - 2.59 (4H, m), 2.85 (2H, d, J = 5.2 Hz), 3.33 - 3.44 (4H ,

m), 4.19 (1H, dd, J = 6.9 Hz, 10.2 Hz), 4.35 (1H, dd, J = 6.9 Hz, 10.2 Hz), 5.36-5 , 49 (1H, m), 7.55 (1H, s).

Example 395

Preparation of ter-butyl (R) -4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2827] (R) -4- [3- (2-chloro-4-nitroim idazol-1-yl) -2-h idroxypropyl I] piperazine-1 ter-butyl carboxylate prepared in Example 364 (6.43 g, 16.49 mmol) was dissolved in 1.4 -dioxane (35 ml). Sodium hydride (730 mg, 18.25 mmol) was added to the solution with cooling in an ice bath, and the resulting solution was stirred at room temperature overnight and then stirred at reflux for 24 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue slowly, the mixture was extracted with methylene chloride twice, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) giving (R) -4- (6nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1 tert-butyl carboxylate (1.23 g, 21% yield) as a white powder.

[2828] Optical purity> 99% e.e.

[2829] [a] d ²⁷ = 11.635 ° (concentration: 1.004, CHCb) [2830] ¹ H NMR (CDCb) δ ppm:

[2831] 1.45 (9H, s), 2.50 - 2.61 (4H, m), 2.85 (2H, d,. J = 5.3 Hz), 3.31 - 3.50 ( 4H,

m), 4.18 (1H, dd, J = 6.9 Hz, 10.2 Hz), 4.35 (1H, dd, J = 8.4 Hz, 10.2 Hz), 5.35-5 , 50

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672/854 (1H, m), 7.55 (1H, s).

Example 396

Preparation of ter-butyl (R) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate [2832] (R) -4 - [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1 ter-butyl carboxylate prepared in Example 368 (376 mg, 0.93 mmol) was dissolved in 1,4-dioxane (10 ml). Sodium hydride (45 mg, 1.12 mmol) was added to the solution with cooling in an ice bath, and the resulting solution was stirred at room temperature for 30 minutes and then stirred at reflux for 24 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added slowly to the residue, and the solution was extracted with ethyl acetate twice. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / acetone = 3/1) giving (R) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] teraz-butyl oxazol-2-ylmethyl) piperazine-1-carboxylate (239 mg, 70% yield) as a white powder.

[2833] Optical purity 99.2% e.e.

[2834] [a] d ²⁷ = 21.073 ^o (concentration: 0.522, CHCb) [2835] ¹ H NMR (CDCb) δ ppm:

[2836] 1.45 (9H, s), 1.61 (3H, s), 2.45 - 2.64 (5H, m), 2.87 (1H, d, J = 14.9 Hz),

3.29 (4H, br), 3.92 (1H, d, J = 9.7 Hz), 4.33 (1H, d, J = 9.7 Hz), 7.52 (1H, s).

Example 397

Preparation of (S) -2- [4- (4-trifluoromethoxyphenyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2837] To a solution of ( S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethoxyphenyl) piperazin-1-yl] propan-2-ol prepared in Example 369 (5.85 g, 12.61 mmol) in THF (150 ml), sodium hydride (0.66 g, 18.92 mmol) was added with cooling in an ice bath, followed by reflux stirring for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added water and ethyl acetate. The precipitates were removed by filtration, purified by

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673/854 column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) and recrystallized from isopropanol giving (S) -2- [4- (4-trifluoromethoxyphenyl) piperazin-1yl] methyl- 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (2.58 g, 48% yield) as a light yellow solid.

[2838] Optical purity 99.8% e.e.

[2839] [oc] d ²⁶ = 8.80 ° (concentration: 1,000, CHCb) [2840] Melting point 129-130 ° C.

Example 398

Preparation of (S) -2- [4- (4-chlorophenyl) piperazin-1-ilm ethyl] -2-m ethyl 1-6-n itro-2,3 dihydroimidazo [2,1-b] oxazole [2841] (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4-chlorophenyl) piperazin-1 yl] propan-2-ol prepared in Example 370 ( 33.0 g, 79.7 mmol) was dissolved in DMF (300 ml). Sodium hydride (3.7 g, 91.6 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature overnight. Water was added to the reaction mixture, with ice, and ethyl acetate, and the solution was stirred vigorously. The precipitates were removed by filtration, washed with water and ethyl acetate, and dried under reduced pressure to give 23.2 g of a crude light yellow powder. The crude powder was combined with another crude powder synthesized in the same way (50 g), and the mixture was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 50/1) and crystallized from chloride methylene-ethyl acetate giving (S) -2- [4- (4-chlorophenyl) piperazin-1-ylmethyl] -2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazole (45 g , 90% yield) as a white powder.

[2842] Optical purity 99.6% e.e.

[2843] [oc] d ²² = -10.20 ° (concentration: 0.5, CHCb) [2844] Melting point 218-219.6 ° C.

[2845] Using corresponding starting materials, compounds of Examples 399 to 403 were obtained in the same manner as in Example 398.

Example 399 (S) -2- [4- (4-Fluorophenyl) piperazin-1-ylmethyl] -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2846] 42% yield, [a ] d ²⁸ = 2.10 ° (concentration: 0.5, CHCb)

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674/854 [2847] Melting point 178.5-179.5 ° C.

Example 400 (S) -2- [4- (3-Pyridyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2848] yield of 42 %, melting point 145-147.7 ° C.

Example 401 (S) -2- [4- (4-Pyridyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2849] yield of 3 % [2850] ¹ H NMR (CDCb) δ ppm:

[2851] 1.65 (3H, s), 2.62 (1H, d, J = 14.8 Hz), 2.64 - 2.71 (2H, m), 2.79 - 2.89 (2H ,

m), 2.92 (1H, d, J = 14.8 Hz), 3.15 - 3.30 (4H, m), 3.95 (1H, d, J = 9.7 Hz), 4, 33 (1H, d, J = 9.7 Hz), 6.60 (2H, d, J = 6.2 Hz), 7.53 (1H, s), 8.26 (2H, d, J = 6 , 2 Hz).

Example 402 (S) -2- [4- (4-fluoromethylphenyl) piperazin-1-ylmethyl] -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2852] Melting point 175.8- 176.6 ° C.

Example 403 (S) -2- [4- (4-cyanophenyl) piperazin-1-ylmethyl] -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2853] Melting point 211-211, 5 ° C.

Example 404

Preparation of (S) -2- [4- (4-chlorophenyl) piperazin-1-ylmethyl] -6-nitro-2,3-dihydroimidazo [2,1b] oxazole [2854] 1- (4) dihydrochloride -chlorophenyl) piperazine (1.31 g, 4.86 mmol) to a sodium hydroxide solution, and the resulting mixture was extracted with methylene chloride. The extract was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure giving 1- (4-chlorophenyl) piperazine.

[2855] Then, a mixture of 1- (4-chlorophenyl) piperazine obtained, (R) -2-chloro1- (oxiran-2-ylmethyl) -4-nitroimidazole prepared in Example 9 (763 mg, 3.75 mmol ) and DMF (5 ml) was stirred at 70 ° C for 6 hours. Sodium hydride (219 mg, 5.48 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 2 hours. Ice water was added to the reaction mixture, and precipitates were removed by filtration. The resulting solids were

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675/854 recrystallized from acetone / water giving (S) -2- [4- (4-chlorophenyl) piperazin-1-ylmethyl] -6nitro-2,3-dihydroimidazo [2,1-b] oxazole (250 mg, yield 18%) as a light yellow powder.

[2856] Melting point 183-183.5 ° C.

Example 405

Preparation of 4-trifluoromethoxybenzyl (28)] (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate [2857] (S) -4 - 4-Trifluoromethoxybenzyl [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1 carboxylate prepared in Example 390 (4.3 g, 8.24 mmol) was dissolved in DMF (13 ml). Sodium hydride (430 mg, 10.7 mmol) was added to the solution, followed by stirring at the same temperature for 2 hours with cooling in an ice bath. Ethyl acetate (4.3 ml) and water (30 ml) were added to the reaction mixture in this order, and the solution was stirred for 30 minutes. The precipitates were removed by filtration and washed with water. The obtained solids were recrystallized from ethyl acetate / isopropyl ether and then recrystallized from isopropyl alcohol giving (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole- 4-trifluoromethoxybenzyl 2-ylmethyl) piperazine-1carboxylate (3.15 g, 79% yield) as a white powder.

[2858] Melting point 139.5-140.5 ° C [2859] Optical purity> 99.5% e.e.

[2860] [a] d ²⁷ = 18.04 ° (concentration: 1.020, CHCb) [2861] ¹ H NMR (CDCb) δ ppm:

[2862] 1.60 (3H, s), 2.39 - 2.75 (5H, m), 2.87 (1H, d, J = 14.9 Hz), 3.14 - 3.56 (4H ,

m), 3.93 (1H, d, 9.7 Hz), 4.29 (1H, d, J = 9.7 Hz), 5.10 (2H, s), 7.19 (2H, d, J = 8.6 Hz), 7.36 (2H, d, J = 8.6 Hz), 7.54 (1H, s).

Example 406

Preparation of 3- (4-trifluoromethylphenyl) -2-propenyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate -2-propenyl [2863] 3- (4-trifluoromethylphenyl) -2- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-1 carboxylate -2- propenyl prepared in Example 391 (13.2 g,

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676/854

24.81 mmol) was dissolved in DMF (40 ml). Sodium hydride (1.19 g, 29.78 mmol) was added to the solution, followed by stirring for 1.5 hours with cooling in an ice bath. Ethyl acetate (13 ml) and water (92 ml) were added to the reaction mixture in this order, followed by stirring for 30 minutes. The precipitates were removed by filtration, washed with water and purified by column chromatography on silica gel (ethyl acetate) giving (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] 3- (4trifluoromethylphenyl) -2-propenyl oxazol-2-ylmethyl) piperazine-1-carboxylate (10.17 g, 83% yield) as a light yellow powder.

[2864] Melting point 132-133 ° C [2865] Optical purity 99.0% e.e.

[2866] [a] d ²⁷ = -21.73 ° (concentration: 0.866, CHCb) [2867] ¹ H NMR (CDCb) δ ppm:

[2868] 1.62 (3H, s), 2.48 - 2.75 (5H, m), 2.88 (1H, d, J = 14.9 Hz), 3.15 - 3.57 (4H ,

m), 3.94 (1H, d, J = 9.7 Hz), 4.29 (1H, d, J = 9.7 Hz), 4.75 (2H, d, J = 1.15 Hz, 6.0 Hz),

6.29 - 6.42 (1H, m), 6.64 (1H, d, J = 15.9 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.52 - 7 , 62 (3H, m).

[2869] Using corresponding starting materials, the compound of Example 407 was obtained in the same way as in Example 406.

Example 407 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate 3- (4-trifluoromethoxyphenyl) -2 -propenyl [2870] Melting point 91 -93 ° C [2871] [a] d ²⁷ = -21.88 ° (concentration: 0.786, CHCb) [2872] ¹ H NMR (CDCb) δ ppm:

[2873] 1.54 (3H, s), 2.38-2.71 (5H, m), 2.84 (1H, d, J = 14.9 Hz), 3.13 - 3.54 (4H ,

m), 3.92 (1H, d, J = 9.7 Hz), 4.29 (1H, d, J = 9.7 Hz), 4.73 (2H, dd, J = 1.2 Hz, 6.2 Hz), 6.15-6.33 (1H, m), 6.60 (1H, d, J = 16.0 Hz), 7.16 (2H, d, J = 8.7 Hz) , 7.40 (2H, d, J = 8.7 Hz), 7.53 (1H, s).

Example 408

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677/854

Preparation of (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole [2874] (S) -4- (2-methyl dihydrochloride) -6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) tert-butyl piperazine-1-carboxylate prepared in Example 393 (1.46 g, 3.98 mmol) was dissolved in trifluoroacetic acid (30 ml), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml). A solution of a saturated hydrogen chloride in ethyl acetate was added to the solution, followed by stirring for 30 minutes with cooling in an ice bath. The precipitates were removed by filtration giving (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride (994 mg, yield 73%) as a yellow powder.

[2875] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[2876] 1.63 (3H, s), 2.80 - 3.36 (6H, m), 4.11 (1H, d, J = 11.0 Hz), 4.25 - 4.98 (5H ,

m), 8.15 (1H, s), 9.31 (2H, br).

Example 409

Preparation of (S) -6-nitro-2- [4- (4-trifluoromethylbenzyl) piperazin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole [2877] A mixture of (S) -4- Ter-butyl (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) piperazine-1-carboxylate prepared in Example 394 (100 mg, 0.27 mmol) and trifluoroacetic acid (2 ml) it was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (1 ml, 7.17 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), and the solution received the addition of 4trifluoromethylbenzaldehyde (148 mg, 0.85 mmol), sodium cyanotrihydroborate (53 mg, 0.85 mmol), and acetic acid (49 μΙ, 0 , 85 mmol) in that order, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium hydrogen carbonate solution was added to the residue, and the solution was extracted with methylene chloride twice. The organic phases were combined, washing with a saturated solution

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678/854 of sodium hydrogen carbonate and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 1/1) giving (S) -6-nitro-2- [4- (4trifluoromethylbenzyl) piperazin-1-ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole (53 mg, 46% yield) as a light yellow powder.

[2878] Melting point 149-150 ° C.

Example 410

Preparation of (S) -2- [4- (biphenyl 1-4-yl ethyl) piperazin-1-i im ethyl] -6-n itro-2,3 dihydroimidazo [2,1-b] oxazole [2879] A mixture of ter-butyl (S) -4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) piperazine-1-carboxylate prepared in Example 394 (7.2 g, 20 , 26 mmol), trifluoroacetic acid (24 ml) and methylene chloride (72 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (100 ml), then neutralized with triethylamine (20 ml, 143.49 mmol). The solution was concentrated under reduced pressure, and the residue was dissolved in methanol (72 ml). To the solution, 4-phenylbenzaldehyde (7.38 g, 40.52 mmol), sodium cyanotrihydroborate (3.82 g, 60.78 mmol), and acetic acid (3.48 ml, 60.78 mmol) were added to this solution. order, followed by stirring at room temperature for 24 hours. The precipitates were removed by filtration, washed with methanol, and purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) giving (S) -2- [4- (biphenyl-4ylmethyl) piperazin -1-ylmethyl] -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (5.52 g, 65% yield) as a yellow powder.

[2880] Optical purity> 99.0% e.e.

[2881] [a] d ²⁸ = -28.261 ° (concentration: 0.046, DMSO) [2882] Melting point 207-208 ° C.

Example 411

Preparation of (R) -2- [4- (biphenyl-4-i Imethyl) piperazin-1 -i Imethyl] -6-n itro-2,3dihydroimidazo [2,1-b] oxazole

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679/854 [2883] A mixture of ter-butyl (R) -4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate prepared in Example 395 ( 101.5 mg, 0.29 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (2 ml, 14.35 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (156 mg, 0.86 mmol), sodium cyanotrihydroborate (53 mg, 0.84 mmol) and acetic acid (0.05 ml, 0.87 mmol) were added in this order, followed by stirring. at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Saturated sodium hydrogen carbonate solution was added to the residue, and the solution was extracted with methylene chloride twice. The organic phases were combined, washing with a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate) giving (R) -2- [4 (biphenyl-4-ylmethyl) piperazin-1-ylmethyl] -6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (56 mg, 46% yield) as a white powder.

[2884] [a] d ²⁸ = 28.261 ° (concentration: 0.046, DMSO).

[2885] Melting point 224-225 ° C [2886] Using corresponding starting materials, the compound of Example 412 was obtained in the same way as in Example 411.

Example 412 (R) -6-Nitro-2- [4- (4-trifluoromethylbenzyl) piperazin-1-ylmethyl] -2,3-dihydroimidazo [2,1b] oxazole [2887] 48% yield, melting point 141 -143 ° C.

Example 413

Preparation of (S) -2-methyl-6-nitro-2- [4- (4'-trifluoromethyl Ibifen i-4-iimethyl) piperazin-1 ylmethyl] -2,3- dihydroimidazo [2,1-b] oxazol [2888] A mixture of (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2

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680/854 ylmethyl) tert-butyl piperazine-1-carboxylate prepared in Example 393 (1.7 g, 4.6 mmol), trifluoroacetic acid (10 ml) and methylene chloride (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml). To the solution, 4'-trifluoromethylbiphenyl-4-carboaldehyde (2.3 g, 9.19 mmol), sodium cyanotrihydroborate (580 mg, 9.23 mmol) and acetic acid (0.55 ml, 9.62 mmol) were added ) in this order, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Saturated sodium hydrogen carbonate solution was added to the residue, and the solution was extracted with methylene chloride twice. The organic phases were combined, washing with a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving (S) 2-methyl-6-nitro-2- [4 - (4'-trifluoromethylbiphenyl-4-ylmethyl) piperazin-1-ylmethyl] -2,3 dihydroimidazo [2,1-b] oxazole (1.47 g, 63% yield) as a white powder.

[2889] [oc] d ²⁸ = 1.831 ⁰ (concentration: 0.71, CHCb) [2890] ¹ H NMR (CDCb) δ ppm:

[2891] 1.60 (3H, s), 2.20 - 2.45 (4H, m), 2.45 - 2.65 (4H, m), 2.50 (1H, d, J = 15, 0

Hz), 2.86 (1H, d, J = 15.0 Hz), 3.48 (2H, s), 3.89 (1H, d, J = 10.0 Hz), 4.31 (1H, d, J = 10.0 Hz), 7.37 (2H, d, J = 8.0 Hz), 7.50 - 7.56 (3H, m), 7.68 (4H, s).

[2892] Using corresponding starting materials, compounds of Examples 414 to 417 were obtained in the same manner as in Example 413.

Example 414 (S) -2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzyl) piperazin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole [2893] Melting point 110- 112 ° C.

Example 415 (S) -2- [4- (Biphenyl-4-ylmethyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1 b] oxazole

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681/854 [2894] Melting point 182-184 ° C.

Example 416 (S) -2-methyl-6-nitro-2- [4- (4-trifluoromethoxybenzyl) piperazin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole [2895] Melting point 137- 138 ° C.

Example 417 (S) -2- {4- [2- (4-chlorophenyl) -4-methylthiazol-5-ylmethyl] piperazin-1-ylmethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1 -b] oxazole [2896] Melting point 174.3-175.5 ° C.

Example 418

Preparation of (R) -2- [4- (biphenyl 1-4-yl ethyl) piperazin-1-i Imethyl] -2-m ethyl 1-6-nitro-2,3 dihydroimidazo [2,1-b ] oxazole [2897] A mixture of ter-butyl (R) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate Example 396 (100 mg, 0.27 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (1 ml, 7.17 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (149 mg, 0.82 mmol), sodium cyanotrihydroborate (51 mg, 0.82 mmol) and acetic acid (48 μΙ, 0.82 mmol) were added in this order, followed by stirring at temperature environment for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added with a saturated solution of sodium hydrogen carbonate. The precipitates were removed by filtration and purified by column chromatography on silica gel (ethyl acetate) giving (R) -2- (biphenyl-4-ylmethyl) piperazin-1-ylmethyl) -2-methyl-6-nitro2, 3-dihydroimidazo [2,1-b] oxazole (67 mg, 57% yield) as a light yellow powder.

[2898] Melting point 112-114 ° C.

[2899] Using corresponding starting materials, the compound of Example 419 was obtained in the same way as in Example 418.

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682/854

Example 419 (R) -2-methyl-6-nitro-2- [4- (4-trifluoromethylbenzyl) piperazin-1-ylmethyl] -2,3dihydroimidazo [2,1-b] oxazole [2900] Melting point 93- 95 ° C.

Example 420

Preparation of (S) -2-chloro-1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im ethyl) piperazin-1-yl] ethanone [2901] A mixture of tert-butyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate prepared in Example 393 (1.5 g, 4.1 mmol) and trifluoroacetic acid (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (20 ml), and the solution was added triethylamine (3 ml) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) in that order. A solution of acetyl chlorochloride (0.49 ml, 6.2 mmol) in methylene chloride (2 ml) was added slowly to the mixture with cooling in an ice bath, followed by stirring at room temperature for one day to the other. The reaction mixture was washed with water twice, a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, drying over magnesium sulfate and then filtering. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving (S) -2-chloro-1- [4- (2 -methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] ethanone (600 mg, 43% yield) as a light brown powder.

[2902] ¹ H NMR (CDCb) δ ppm:

[2903] 1.64 (3H, s), 2.50 - 2.70 (3H, m), 2.61 (1H, d, J = 15.0 Hz), 2.70 - 2.90 (1H ,

m), 2.89 (1H, d, J = 15.0 Hz), 3.15-3.55 (3H, m), 3.60-3.75 (1H, m), 3.97 (1H , d, J = 10.0 Hz), 4.03 (2H, s), 4.30 (1H, d, J = 10.0 Hz), 7.55 (1H, s).

Example 421

Preparation of (S) -2- (4-chlorophenoxy) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazin-1-yl] ethanone

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683/854 [2904] A mixture of (S) -2-chloro-1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazin-1 -yl] ethanone prepared in Example 420 (300 mg, 0.87 mmol), 4-chlorophenol (170 mg, 1.32 mmol), potassium carbonate (180 mg, 1.3 mmol) and DMF (5 ml) was stirred at 60 ° C for 3 hours. The reaction mixture was allowed to return to room temperature, then diluted with water. The solution was extracted with ethyl acetate twice. The organic phases were combined, washing with a solution of sodium hydroxide, water and a saturated saline solution in that order, drying over magnesium sulfate and then filtering. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol giving (S) 2- (4-chlorophenoxy) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2ylmethyl) piperazin-1-yl] ethanone (260 mg, 68% yield) as a light brown powder.

[2905] Melting point 179-180 ° C.

Example 422

Preparation of (S) -2- (4-chlorophenylsulfanyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazin-1-yl] ethanone [2906] Using a mixture of (S) -2-chloro-1- [4- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1- yl] ethanone prepared in Example 420 (300 mg, 0.87 mmol) and 4-chlorothiophenol (190 mg, 1.32 mmol) gave (S) -2- (4 chlorophenylsulfanyl) -1- [4- (2- methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] ethanone (80 mg, 20% yield) as a white powder in the same manner as in Example 421.

[2907] Melting point 142-145 ° C.

Example 423

Preparation of (S) - (4-chlorophenyl) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im ethyl) piperazin-1-yl] methanone [2908] A mixture of tert-butyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate prepared in Example 393 (300 mg, 0.82 mmol) and trifluoroacetic acid (6 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was

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684/854 dissolved in methylene chloride (15 ml), and the solution received the addition of triethylamine (2 ml, 14.35 mmol). 4-Chlorobenzoyl chloride (150.7 mg, 0.86 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, water and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether-ethyl acetate giving (S) - (4-chlorophenyl) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2, 1-b] oxazol-2-ylmethyl) piperazin-1yl] methanone (282 mg, 85% yield) as a yellow powder.

[2909] Melting point 173-174 ° C.

[2910] Using corresponding starting materials, the compound of Example 424 was obtained in the same way as in Example 423.

Example 424 (Biphenyl-4-yl) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl) piperazin-1yl] methanone [2911] melting 116-118 ° C.

Example 425

Preparation of [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1yl] phenylmethanone [2912] A mixture of 2- (4-ter- butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-nitro2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 306 (142 mg, 0.39 mmol), trifluoroacetic acid (1 ml) and chloride methylene (1 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (2 ml). Triethylamine (2 ml,

14.35 mmol). Benzoyl chloride (54 μΙ, 0.46 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with a saturated solution of sodium hydrogen carbonate, water and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether giving

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685/854 [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl) piperazin-1-yl] phenylmethanone (72 mg, 50% yield) like a yellow powder.

[2913] Melting point 145-148.7 ° C.

[2914] Using corresponding starting materials it was obtained compounds of the

Examples 426 to 433 in the same way as in Example 425.

Example 426 (4-chlorophenyl) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1yl] methanone [2915] Melting point 150 , 0-155.2 ° C.

Example 427 [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl) piperazin-1-yl] (pyridin-4yl) methanone [2916] ¹ H NMR (CDCb) δ ppm:

[2917] 1.62 (3H, s), 2.25 - 2.75 (4H, m), 2.61 (1H, d, J = 14.9 Hz), 2.88 (1H, d, J =

14.9 Hz), 3.00 - 3.93 (4H, br), 3.95 (1H, d, J = 9.8 Hz), 4.30 (1H, d, J = 9.8 Hz) , 7.26 7.55 (2H, m), 7.59 (1H, s), 8.67 - 8.72 (2H, m).

Example 428

1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -2-phenylethanone [2918] Melting point 175.2- 175.9 ° C.

Example 429

1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -3phenylpropan-1-one [2919] Melting point 166.8-169.1 ° C.

Example 430

1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -2-phenoxyethanone [2920] Melting point 158-160, 6 ° C.

Example 431

2- (4-chlorophenyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-

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1-yl] ethanone [2921] Melting point 184-187 ° C.

Example 432 (Biphenyl-4-yl) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1yl] methanone [2922] ¹ H NMR (CDCb) δ ppm:

[2923] 1.63 (3H, s), 2.45 - 2.80 (4H, m), 2.62 (1H, d, J = 14.9 Hz), 2.90 (1H, d, J =

14.9 Hz), 3.28 - 3.81 (4H, br), 3.95 (1H, d, J = 9.8 Hz), 4.31 (1H, d, J = 9.8 Hz) , 7.34 -

7.50 (5H, m), 7.55 (1H, s), 7.56 - 7.63 (4H, m).

Example 433 [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] - (4trifluoromethylphenyl) methanone [2924] Melting point 161 -162 ° C.

Example 434

Preparation of (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] - (4-trifluoromethylphenyl) methanone [2925] (S) -2-Methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3 dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 408 (2.36 mg, 0.882 mmol) was suspended in methylene chloride (10 ml). Triethylamine (1 ml, 7.17 mmol) was added to the suspension. 4- (Trifluoromethyl) benzoyl chloride (193 mg, 0.926 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, water and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving (S) - [4- (2-methyl-6-nitro -2,3 dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] - (4-trifluoromethylphenyl) methanone (264 mg, 68% yield) as a white powder.

[2926] Melting point 183-184 ° C.

[2927] Using corresponding starting materials it was obtained compounds of the

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687/854

Examples 435 to 438 in the same way as in Example 434, (Compounds in

Examples 435 to 437 were prepared with 2-methyl-6-nitro-2 (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 322)

Example 435 [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) methoxyphenyl) methanone [2928] Melting point 135-137 ° C.

Example 436 [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) methylphenyl) methanone [2929] Melting point 121-122 ° C.

Example 437 [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) trifluoromethylphenyl) methanone [2930] Melting point 122-124 ° C.

Example 438 (S) -2- (4-chlorophenyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo piperazin-1 -yl] - (4piperazin-1-yl] - (4piperazin -1 -yl] - (3 [2,1-b] oxazol-2i Im ethyl) piperazin-1-yl] ethanone [2931] Melting point 189-190 ° C.

Example 439

Preparation of (S) -2- (3,4-dichlorophenoxy) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazin-1- il] ethanone [2932] A mixture of 3,4- (dichlorophenoxy) acetic acid (234 mg, 1.06 mmol) and thionyl chloride (5 ml) was stirred at reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure giving the corresponding acid chloride. This was dissolved in methylene chloride (5 ml).

[2933] The solution was added to a mixture of (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 408 (236 mg, 0.88 mmol), methylene chloride (10 ml), and triethylamine (1 ml, 7.17 mmol) with cooling in an ice bath, followed by stirring at room temperature for

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688/854 hour. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, water and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving (S) -2- (3,4-dichlorophenoxy) -1- [4- (2-methyl- 6nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] ethanone (183 mg, 44% yield) as a white powder.

[2934] Melting point 164-166 ° C.

[2935] Using corresponding starting materials, the compound of Example 440 was obtained in the same way as in Example 439.

Example 440 (S) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -4- (4trifluoromethylphenyl) butan-1-one [2936] Melting point 145-146 ° C.

Example 441

Preparation of (S) -3- (4-chlorophenyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethyl) piperazin-1-yl] propenone [2937] A mixture of 4-chlorokinamic acid (300 mg, 1.64 mmol), 1 hydroxybenzotriazole (HOBT) (240 mg, 1.77 mmol), WSCD (350 mg, 1.83 mmol) and methylene chloride ( 10 ml) stirred at room temperature for 30 minutes received the addition of a mixture of (S) -2-methyl-6-nitro-2- (piperazin-1ylmethyl) -2,3-dihydroimidazo [2,1-b ] oxazole prepared in Example 408 (434 mg, 1.64 mmol), methylene chloride (10 ml), and triethylamine (3.3 ml, 2.37 mmol) with cooling in an ice bath, followed by stirring at room temperature for 3 hours. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, water and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) giving (S) -3- (4-chlorophenyl) -1- [4- (2-methyl-6-nitro-2,3- dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] propenone (180 mg, 26% yield) as a white powder.

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689/854 [2938] Melting point 220-222 ° C.

[2939] Using corresponding starting materials, compounds of Examples 442 to 445 were obtained in the same manner as in Example 441.

Example 442 (S) -3- (chlorophenyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im ethyl) piperazin-1-yl ] propan-1-one [2940] Melting point 177-178 ° C.

Example 443 (S) -4- (4-chlorophenyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im ethyl) piperazin-1 -il] butan-1-one [2941] Melting point 146-147 ° C.

Example 444 (S) -3- (3,4-Dichlorophenyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1- il] propenone [2942] Melting point 213-215 ° C.

Example 445 (S) -5- (4-chlorophenyl) -1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im ethyl) piperazin-1 -il] pentan-1 -one [2943] Melting point 108-111 ° C.

Example 446

Preparation of 1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin1 -yl] -2- (4-tolyl) ethanone [2944 ] A mixture of 2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 322 (240 mg, 0.79 mmol), DMF (5 ml) and triethylamine (0.22 ml, 1.58 mmol) received the addition of p-tolylacetic acid (140 mg, 0.93 mmol) and WSCD (180 mg, 0.93 mmol) in that order, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water twice, a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated

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690/854 with diethylether giving 1- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] -2- (4-tolyl) ethanone (172 mg, 64% yield) as a white powder.

[2945] Melting point 213-214 ° C.

[2946] Using corresponding starting materials, the compound of Example 447 was obtained in the same manner as in Example 446.

Example 447 (4-dimethylaminophenyl) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im ethyl] piperazin-1-yl] methanone [2947] Spot melting temperature 204-207 ° C.

Example 448

Preparation of (S) -2- {4- [3- (4-chlorophenyl) propane-1-sulfonyl] piperazin-1-ylmethyl} -2-methyl6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2948] A mixture of ter-butyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate prepared in the Example 393 (300 mg, 0.82 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). Triethylamine (3 ml, 21.52 mmol) was added to the solution, followed by stirring at room temperature for 10 minutes, and then 3- (4-chlorophenyl) propane-1-sulfonyl chloride (300 mg, 1 , 19 mmol), followed by stirring at room temperature for 3 days. The reaction mixture was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving (S) -2- {4- [3- (4-chlorophenyl) propane-1-sulfonyl] piperazin1 -ylmethyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (330 mg, 84% yield) as a white powder.

[2949] Melting point 150-151 ° C.

[2950] Using 2- (4-ter-butoxycarbonylpiperazin-1-ilm ethyl) -2-m ethyl 1-6-n itro-2,3 dihydroimidazo [2,1-b] oxazole prepared in Example 306, compounds were obtained From

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691/854

Examples 449 and 450 in the same way as in Example 448.

Example 449 2- [4- (4-chlorobenzenesulfonyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [2951] Melting point 202-204 ° C.

Example 450 2- [4- (4-chlorophenylmethanesulfonyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2952] Melting point 215-217 ° C.

Example 451

Preparation of (S) -2- {4- [2- (4-chlorophenyl) ethanesulfonyl] piperazin-1-ylmethyl} -2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazole [2953] A mixture of (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) - dihydrochloride

2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 408 (236 mg, 0.88 mmol) and DMF (3 ml) received the addition of potassium carbonate (500 mg, 3.62 mmol) and chloride of 2 (4-chlorophenyl) ethanesulfonyl (240 mg, 1 mmol) in that order, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with water three times and brine, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving (S) 2- {4- [2- (4-chlorophenyl) ethanesulfonyl] piperazin-1-ylmethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole (100 mg, 26% yield) as a white powder.

[2954] Melting point 192-193 ° C.

[2955] Using (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3 dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 408, compounds of Examples of 452 to 454 in the same manner as in Example 451. Also, using 2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 322 the compound of Example 455 was obtained in the same manner as in Example 451.

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692/854

Example 452 (S) -2- [4- (4-chlorobenzenesulfonyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2956] Melting point 216- 218 ° C.

Example 453 (S) -2- [4- (4-chlorophenylmethanesulfonyl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2957] Melting point 204- 206 ° C.

Example 454 (S) -2- {4- [4- (4-chlorophenyl) butane-1-sulfonyl] piperazin-1-ylmethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2958] Melting point 176-177 ° C.

Example 455 2- {4- [2- (4-chlorophenyl) ethanesulfonyl] piperazin-1-ylmethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [2959] Melting point 182 -184 ° C.

Example 456

Preparation of 4-trifluoromethylbenzyl (S) -4- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [2960] A mixture of (S) -4- Tert-butyl (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) piperazine-1-carboxylate prepared in Example 394 (300 mg, 0.84 mmol) and methylene chloride (2 ml ) received the addition of trifluoroacetic acid (1 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (1 ml) and neutralized with triethylamine (1 ml).

[2961] A mixture of 4- (trifluoromethyl) benzyl alcohol (297 mg, 1.69 mmol), DMF (1 ml), and 1,1'-carbonyldiimidazole (274 mg, 1.69 mmol) was added to the solution. ) stirred at room temperature for 1 hour, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate twice. The organic phases were combined,

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693/854 washing with water twice and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving (S) -4- (6-nitro-2,3- 4-trifluoromethylbenzyl dihydroimidazo [2,1-b] oxazol-2-methyl) piperazine-1-carboxylate (273 mg, 71% yield) as a white powder.

[2962] [a] d ²⁸ = -14.851 ⁰ (concentration: 0.404, CHCb) [2963] Melting point 125-125.5 ° C.

Example 457

Preparation of 4-trifluoromethylbenzyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) 1-carboxylate [2964] A mixture of (S ) Ter-butyl -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) piperazine-1-carboxylate prepared in Example 393 (1.87 g, 5, 09 mmol) and methylene chloride (20 ml) received the addition of trifluoroacetic acid (20 ml), followed by stirring for 5 minutes, and then this was concentrated under reduced pressure. The residue was dissolved in DMF (20 ml). A mixture of 1,1'-carbonyldiimidazole (1.76 g, 10.9 mmol), 4 (trifluoromethyl) benzyl alcohol (1.92 g, 10.9 mmol) and DMF (20 ml) was added to the solution. stirred at room temperature for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The organic phases were combined, washing with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / acetone = 3/1), recrystallized from isopropyl alcohol. The resulting solids were removed by filtration and then dried under reduced pressure giving (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1carboxylate of 4-trifluoromethylbenzyl (1.48 g, 53% yield) as a light yellow powder.

[2965] Melting point 140.4-141.6 ° C [2966] Optical purity 99.9% e.e.

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694/854 [2967] ¹ H NMR (CDCb) δ ppm:

[2968] 1.62 (3H, s), 2.52 - 2.69 (5H, m), 2.88 (1H, d, J = 14.9 Hz), 3.43 (4H, br),

3.93 (1H, d, J = 9.7 Hz), 4.28 (1H, d, J = 9.7 Hz), 5.16 (2H, s), 7.44 (2H, d, J = 8.1 Hz), 7.53 (1H, s), 7.61 (2H, d, J = 8.1 Hz).

Example 458

Preparation of 1,3,3-trimethyl-2-oxo (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate -2,3-dihydro-1 H-indol-5-imethyl [2969] To a mixture of 3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-ylmethyl (S) - 4- (2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate (300 mg, 0.62 mmol) and DMF (3 ml), were added if sodium hydride (27 mg, 0.68 mmol), followed by stirring for 30 minutes with cooling in an ice bath. Methyl iodide (97 mg, 0.68 mmol) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washing with water twice and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate) giving (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [ 1,3,3-trimethyl-2-oxo-2,3-dihydro-1 H-indol-5-ylmethyl 2,1-b] oxazol2-ylmethyl) piperazine-1-carboxylate (140 mg, 45%) as a light yellow powder.

[2970] Melting point 80-100 ° C (decomposition).

[2971] Using corresponding starting materials, the compound of Example 459 was obtained in the same way as in Example 458.

Example 459 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 1-methyl-2-oxo-1-piperazine-1-carboxylate , 2,3,4-tetrahydroquinol in-6-iimethyl [2972] Melting point 189-190 ° C.

Example 460

Preparation of 3,5-dichlorobenzyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate

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695/854 [2973] To a mixture of (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) dihydrochloride -

2.3- dihydroimidazo [2,1-b] oxazole prepared in Example 408 (300 mg, 0.88 mmol) and DMF (3 ml), triethylamine (270 mg, 2.67 mmol) was added for neutralization. A mixture of 3,5-dichlorobenzyl alcohol (180 mg, 1.02 mmol), DMF (3 ml) and 1, T-carbonyldiimidazole (180 mg, 1.11 mmol) stirred at room temperature for 2 hours was added to the solution , followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washing with water twice and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate) giving (S) -4- (2-methyl-6-nitro-

2.3- 3,5-dichlorobenzyl dihydrimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate (220 mg, 53% yield) as a white powder.

[2974] Melting point 129-130 ° C.

Example 461

Preparation of 3- (3-trifluoromethylphenyl) -2- (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate maleate propenyl [2975] Using (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate prepared in Example 393 (1.09 g, 2.97 mmol) (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1- was obtained 3- (3-trifluoromethylphenyl) -2-propenyl carboxylate maleate (945 mg, 63%) as a white powder in the same manner as in Example 344.

[2976] Melting point 136-138 ° C.

[2977] Using corresponding starting materials, compounds of Examples 462 to 465 were obtained in the same manner as in Example 461.

Example 462 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [(E) -3-methyl maleate -3- (3-trifluoromethylphenyl)] - 2-propenyl [2978] Melting point 142-143 ° C.

Example 463

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696/854 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate 3- (3-chlorophenyl) maleate -2-propenyl [2979] Melting point 150-151 ° C.

Example 464 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate 3- (2,4,6 -trifluorophenyl) -2-propenyl [2980] Melting point 158-159 ° C.

Example 465 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylate [(Z) -3-methyl maleate -3- (3-trifluoromethylphenyl)] - 2-propenyl [2981] Melting point 124-125 ° C.

Example 466

Preparation of 4-fluorobenzyl (R) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate [2982] Using (R) - 4-fluorobenzyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) piperazine-1-carboxylate prepared in Example 396 (106 mg, 0.29 mmol) obtained 4-fluorobenzyl (R) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate (79 mg, 66% yield ) as a white powder in the same way as in Example 457.

[2983] [oc] d ²⁸ = 19.70 ° (concentration: 1.066, CHCb) [2984] Melting point 167-169 ° C.

Example 467

Preparation of (S) -4- (2-methyl-6nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine [3- (4-trifluoromethylphenyl) -2-propenyl] amide -1-carboxylic [2985] A mixture of ter-butyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate prepared in Example 393 (926 mg, 2.52 mmol), trifluoroacetic acid (10 ml) and methylene chloride (3 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (3 ml) and neutralized with triethylamine (2 ml, 14.35 mmol). A mixture of 3- (4

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697/854 trifluoromethylphenyl) -2-propenylamine (761 mg, 3.78 mmol), 1, T-carbonyldiimidazole (613 mg, 3.78 mmol) and DMF (3 ml) stirred at room temperature overnight was added, followed by stirring at room temperature overnight. Water was added to the reaction mixture followed by extraction with ethyl acetate. The extract was washed with water three times and a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving [3- (4-trifluoromethylphenyl) -2-propenyl] amide to (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylic acid (1.2 g, 96% yield) as a light yellow powder.

[2986] Melting point 105-107 ° C.

[2987] Using 2- (4-ter-butoxycarbonylpiperazin-1-yl) methyl-2-methyl-6-n-itro-2,3dihydroimidazo [2,1-b] oxazole prepared in Example 306, compounds of the Examples 468 to 470 in the same way as in Example 467.

Example 468 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazine-1-carboxylic acid (4-trifluoromethylbenzyl) [2988] Melting point 201 - 202.5 ° C.

Example 469 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethyl) piperazine-1-carboxylic acid (4-trifluoromethylphenyl) [2989] Melting point 216- 217 ° C.

Example 470 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazine-1-carboxylic acid (4-chloro-3-trifluoromethylphenyl) [2990] Point melting temperature 222-224 ° C.

Example 471

Preparation of (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (2991] (S) dihydrochloride -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3

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698/854 dihydroimidazo [2,1-b] oxazole prepared in Example 408 (236 mg, 0.88 mmol) was dissolved in a mixture of methylene chloride (15 ml) and triethylamine (2 ml, 14.35 mmol). Cyclohexyl isocyanate (120 mg, 0.96 mmol) was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving acid (S) -4- (2-methyl) cyclohexylamide -6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylic (164 mg, 47%) as a light yellow powder.

[2992] Melting point 98-101 ° C.

[2993] Using 2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 322, compounds of Examples 472 to 476 of same way as in Example 471.

Example 472 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (4-methoxyphenyl) [2994] Melting point 167- 168 ° C.

Example 473 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (4-chlorophenyl) [2995] Melting point 185- 188 ° C (decomposition).

Example 474 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethyl) piperazine-1-carboxylic acid (3-trifluoromethylphenyl) [2996] Melting point 183- 184 ° C.

Example 475 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (3,4-dichlorophenyl) [2997] Melting point 212-214 ° C (decomposition).

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699/854

Example 476 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (4-methylphenyl) [2998] Melting point 202- 203 ° C (decomposition).

Example 477

Preparation of (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylic acid (4-trifluoromethylphenyl) [2999] dihydrochloride of (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 408 (236 mg, 0.88 mmol) was dissolved in a mixture of methylene chloride (5 ml) and triethylamine (2 ml, 14.35 mmol). A mixture of 4-aminobenzotrifluoride (142 mg, 0.882 mmol), 1,1'-carbonyldiimidazole (143 mg, 0.882 mmol) and DMF (6 ml) stirred at room temperature overnight was added to the solution, followed by stirring at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 30/1) giving (S) -4- (2-) acid (4trifluoromethylphenyl) amide methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethyl) piperazine-1-carboxylic (90 mg, 23% yield) as a white powder.

[3000] Melting point 150-152.5 ° C.

[3001] Using corresponding starting materials, compounds of Examples 478 to 481 were obtained in the same manner as in Example 477.

Example 478 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (4-methoxyphenyl) [3002] Point melting range 185.5-187.5 ° C.

Example 479 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazine-1-carboxylic acid (4-trifluoromethylbenzyl) amide

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700/854 [3003] Melting point 101 -103.6 ° C.

Example 480 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (4-chlorophenyl) [3004] Point melting temperature 156-159 ° C (decomposition).

Example 481 (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylic acid (4-methylphenyl) [3005] Point melting temperature 207-210 ° C (decomposition).

Example 482

Preparation of (S) -4- (2-methyl-6-nitro-) N-methyl-N- (4-trifluoromethylphenyl) amide

2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylic [3006] A mixture of (S) -4- (2-methyl-6-) acid (4-trifluoromethylphenyl) amide nitro-

2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1-carboxylic acid prepared in Example 477 (200 mg, 0.44 mmol), DMF (4 ml), and sodium hydride (26 mg , 0.66 mmol) was stirred at room temperature for 1.5 hours. Methyl iodide (0.5 ml, 0.76 mmol) was added to the mixture, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) giving N-methyl-N- (4trifluoromethylphenyl) acid amide (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol2-ylmethyl) piperazine-1-carboxylic (35 mg, 17% yield) as a white powder.

[3007] Melting point 100.4-102.4 ° C.

Example 483

Preparation of (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2iImethyl) piperazin-1 -yl] - [4- (4-trifluoromethylphenyl) piperidin -1 -yl] methanone [3008] A mixture of (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazine-1-carboxylate ter -butyl prepared in Example 393 (1.17 g, 3.32

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701/854 mmol), trifluoroacetic acid (5 ml) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). Triethylamine (5 ml, 35.87 mmol) was added to the resulting solution, followed by stirring at room temperature for 10 minutes. The solution was concentrated under reduced pressure, the residue was dissolved in DMF (15 ml). Potassium carbonate (920 mg, 6.64 mmol) and a solution of 4- (4trifluoromethylphenyl) piperidine-1-carbonyl chloride (1.07 g, 3.65 mmol) in DMF (10 ml) with cooling in an ice bath, followed by stirring at room temperature overnight. Water was added to the reaction mixture followed by extraction with ethyl acetate. The extract was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 30/1) giving (S) - [4- (2-methyl-6-nitro) -2,3 dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] - [4- (4-trifluoromethylphenyl) pipendin-1yl] methanone (575 mg, 33% yield) as a white powder .

[3009] Melting point 179.1-181.9 ° C.

Example 484

Preparation of (S) - [4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridin-1-yl] - [4- (2-methyl-6-nitro-2,3dihydroimidazo [2,1- b] oxazol-2-ylmethyl) piperazin-1-yl] methanone [3010] A mixture of (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) dihydrochloride -

2,3-dihydroimidazo [2,1-b] oxazole prepared in Example 408 (401 mg, 1.5 mmol), DMF (8 ml) and potassium carbonate (750 mg, 5.4 mmol) was stirred at room temperature for 10 minutes. To the reaction mixture, a solution of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine-1-carbonyl chloride (400 mg, 1.56 mmol) in DMF (3 ml) was slowly added with cooling in an ice bath, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic phase was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol

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702/854 giving (S) - [4- (4-chlorophenyl) -1,2,3,6-tetrahydropyrid in-1 -yl] - [4- (2-methyl-6-nitro-2,3dihydroimidazo [2 , 1-b] oxazol-2-ylmethyl) piperazin-1-yl] methanone (380 mg, 53% yield) as a light yellow powder.

[3011] Melting point 161-162 ° C.

[3012] Using (S) -2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 408 gave compounds of Examples 485 and 486 in the same manner as in Example 484. Also, using 2-methyl-6-nitro-2- (piperazin-1-ylmethyl) -2,3-dihydroimidazo [2,1-b] oxazole dihydrochloride prepared in Example 322 gave the compound of Example 487 in the same manner as in Example 484.

Example 485 (S) - [4- (4-chlorophenyl) pyridin-1-yl] - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im eti l) piperazin-1-yl] methanone [3013] Melting point 156-159 ° C.

Example 486 (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] - [4- (4trifluoromethylphenyl ) -1,2,3,6-tetrahydropyridin-1-yl] methanone [3014] Melting point 168.4-171.7 ° C.

Example 487 [4- (4-chlorophenyl) piperidin-1-yl] - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i im ethyl 1) piperazin- 1 -il] methanone [3015] Melting point 186-187 ° C.

Example 488

Preparation of (S) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im ethyl) piperazin-1-yl] benzoic acid [3016] (S) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin1-yl] ter-butyl benzoate (300 mg, 0 , 68 mmol) in triluoroacetic acid (10 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, neutralized with triethylamine, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel

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703/854 (methylene chloride / methanol = 20/1), crystallized from methanol-diisopropyl ether giving (S) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2, 1-b] oxazol-2ylmethyl) piperazin-1-yl] benzoic (186 mg, 71% yield) as a white powder. [3017] MS 387 (M ⁺ ) [3018] Melting point 248-252 ° C.

Example 489

Preparation of (S) -2- [4- (2,6-diphenylpyrimidin-4-yl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [3019 ] (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) terp-butyl-1-carboxylate prepared in Example 393 (500 mg, 1 , 36 mmol) was dissolved in methylene chloride (2 ml). Trifluoroacetic acid (10 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and received the addition of methylene chloride (4 ml) and triethylamine (4 ml). The reaction mixture was stirred at room temperature for 5 minutes and then concentrated under reduced pressure, and the residue was dissolved in DMF (5 ml). 4-chloro-2,6-diphenylpyrimidine (400 mg, 1.50 mmol) and DBU (0.2 ml, 1.36 mmol) were added to the solution, followed by stirring at 100 ° C for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and then the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from methylene chloride-diisopropyl ether giving (S) -2 - [4- (2,6diphenylpyrim idin-4-yl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (113 mg, 17% yield ) as a white powder.

[3020] MS 498 (M + H) ⁺ [3021] Melting point 202.5-205.4 ° C.

[3022] Using corresponding starting materials, the compound of Example 490 was obtained in the same way as in Example 489.

Example 490

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704/854 (S) -2- [4- (4,6-Diphenylpyrimidin-2-yl) piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [ 3023] 7% yield, melting point 201.2-205.4 ° C.

Example 491

Preparation of {4- [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] piperazin-1 yl} ter-butyl carbamate [3024] 2-chloro-4-nitro -1 H-imidazole (2.05 g, 13.9 mmol), tert-butyl 4- (2-methyloxyran-2ylmethyl) piperazin-1-yl) carbamate (3.14 g, 11.6 mmol) and hydrogen carbonate sodium (1.46 g, 17.4 mmol) in 1-propanol (13 ml) were stirred under heating for 6 hours. The reaction mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / acetone = 2/1) giving {4- [3 (2-chloro-4-nitroimidazole- Terbutyl 1-yl) -2-hydroxy-2-methylpropyl] piperazin-1-yl} carbamate (1.55 g, 32% yield) as a white powder.

[3025] ¹ H NMR (CDCb) δ ppm:

[3026] 1.12 (3H, s), 1.46 (9H, s), 2.36 (1H, d, J = 13.9 Hz), 2.50 (1H, d, J = 13.9

Hz), 2.64 - 2.84 (8H, m), 3.32 (1H, s), 3.96 (2H, s), 5.46 (1H, br), 8.03 (1H, s ).

Example 492

Preparation of {4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazin-1 yl} ter-butyl carbamate (alternative synthesis of the compound of Example 491) [ 3027] Using 2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 6 (4.36 g, 20.0 mmol) and ter-butyl piperazin-1-ylcarbamate (4, 44 g, 22.0 mmol) {4- [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] piperazin-1 yl} ter-butyl carbamate ( 6.08 g, 72% yield) as a white powder in the same manner as in Example 365.

Example 493

Preparation of ter-butyl [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1yl] carbamate

Petition 870190039560, of 26/04/2019, p. 713/876

705/854 [3028] Using {4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazin-1-yl} ter-butyl carbamate prepared in Example 492 ( 6.87 g,

16.4 mmol) ter-butyl [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) piperazin-1-yl] carbamate (2, 71 g, 43% yield) as a white powder in the same manner as in Example 393.

[3029] ¹ H NMR (CDCb) δ ppm:

[3030] 1.43 (9H, s), 1.60 (3H, s), 2.36 (1H, d, J = 14.0 Hz), 2.52 - 2.90 (9H, m),

3.90 (1H, d, J = 9.7 Hz), 4.27 (1H, d, J = 9.7 Hz), 5.35 (1H, br), 7.53 (1H, s).

Example 494

Preparation of benzyl [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1yl] carbamate [3031] A mixture of [4- (2 -methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] benzyl carbamate prepared in Example 493 (150 mg, 0.39 mmol) and trifluoroacetic acid (4 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (4 ml) and neutralized with triethylamine (4 ml, 28.7 mmol). Subsequently, benzyl chloroformate (100 mg, 0.59 mmol) was added to the solution with cooling in an ice bath, followed by stirring at room temperature for 2 hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture. The mixture was extracted with methylene chloride. The extract was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / acetone = 1/1) giving [4- (2-methyl-6-nitro-2,3 -diidroim idazo [2,1-b] oxazol-2-ylmethyl) piperazin-1 yl] benzyl carbamate (6.5 mg, 4% yield) as a light yellow powder.

[3032] ¹ H NMR (CDCb) δ ppm:

[3033] 1.60 (3H, s), 2.53 - 2.90 (10H, m), 3.89 (1H, d, J = 9.6 Hz), 4.27 (1H, d, J =

9.6 Hz), 5.11 (2H, s), 5.88 (1H, br), 7.25 - 7.34 (5H, m), 7.52 (1H, s).

Example 495

Preparation of N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazinPetition 870190039560, of 26/04/2019, p. 714/876

706/854

-yl] -N- (4-trifluoromethoxybenzylidene) amine [3034] A mixture of [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1- il] ter-butyl carbamate prepared in Example 493 (40 mg, 0.11 mmol), 4-trifluoromethoxybenzaldehyde (24 mg, 0.13 mmol), trifluoroacetic acid (0.08 ml) and methylene chloride (1 ml) it was stirred at room temperature for 3 hours. The mixture received the addition of a saturated solution of sodium hydrogen carbonate for neutralization, followed by extraction with methylene chloride. The solution was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 3/1) giving N- [4- (2-methyl-6-nitro) -2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] N- (4-trifluoromethoxybenzylidene) amine (19 mg, 40% yield) as a white powder.

[3035] Melting point 189.2-190.9 ° C.

Example 496

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- {4 - [(4trifluoromethylbenzylidene) amino] piperazin-1-yl} propan-2-ol [ 3036] A mixture of (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (218 mg, 1 mmol), N- (piperazin-1-yl) - N- (4trifluoromethylbenzylidene) amine (283 mg, 1.1 mmol) and DMF (2 ml) was stirred at 70-80 ° C for 7 hours. The reaction mixture was allowed to return to room temperature and then received the addition of water, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water 3 times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / acetone = 1/1) giving (S) -1- (2-chloro4-nitroimidazole-1- il) -2-methyl-3- {4 - [(4-trifluoromethylbenzylidene) amino] piperazin-1yl} propan-2-ol (402 mg, 85% yield) as a light yellow powder.

[3037] [oc] d ²⁷ = 19.01 ° (concentration: 1.010, CHCb) [3038] ¹ H NMR (CDCb) δ ppm:

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707/854 [3039] 1.18 (3H, s), 2.42 (1H, d, J = 13.9 Hz), 2.57 (1H, d, J = 13.9 Hz), 2.71 -2.95 (4H, m), 3.10 - 3.33 (5H, m), 4.02 (2H, s), 7.51 (1H, s), 7.58 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8.4 Hz), 8.05 (1H, s).

Example 497

Preparation of (S) - {4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazin1-yl} ter-butyl carbamate [3040] Using (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (29.8 g, 137 mmol) and ter-butyl piperazin-1-ylcarbamate (28.9 g, 144 mmol) ter-butyl (S) - {4- [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] piperazin-1-yl} carbamate (36, 68 g, 64% yield) as a white powder in the same manner as in Example 496.

[3041] [oc] d ²⁷ = 17.793 ° (concentration: 1.006, CHCb) [3042] ¹ H NMR (CDCb) δ ppm:

[3043] 1.12 (3H, s), 1.45 (9H, s), 2.36 (1H, d, J = 14.0 Hz), 2.50 (1H, d, J = 14.0

Hz), 2.64 - 2.84 (8H, m), 3.32 (1H, s), 3.97 (2H, s), 5.47 (1H, br), 8.04 (1H, s ).

[3044] Using corresponding starting materials, compounds of Examples 498 to 500 were obtained in the same manner as in Example 497.

Example 498 (S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- {4 - [(4-trifluoromethoxy benzylidene) amino] piperazin-1-yl} propan-2- ol [3045] [a] d ²⁷ = 12.326 ° (concentration: 1.006, CHCb) [3046] ¹ H NMR (CDCb) δ ppm:

[3047] 1.17 (3H, s), 2.41 (1H, d, J = 13.9 Hz), 2.56 (1H, d, J = 13.9 Hz), 2.71 -2, 95 (4H, m), 3.14 - 3.29 (5H, m), 4.01 (2H, s), 7.19 (2H, d, J = 8.0 Hz), 7.50 (1H , s), 7.62 (2H, d, J = 8.0 Hz), 8.05 (1H, s).

Example 499 (S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- {4 - [(5-trifluoromethylbenzofuran) -2ylmethylene) amino] piperazin-1-yl} propan- 2-ol [3048] ¹ H NMR (CDCb) δ ppm:

[3049] 1.18 (3H, s), 2.43 (1H, d, J = 14.0 Hz), 2.58 (1H, d, J = 14.0 Hz), 2.73 - 2, 82

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708/854 (2H, m), 2.86 - 2.95 (2H, m), 3.17 (1H, s), 3.31 (4H, s), 4.03 (2H, s), 6 , 82 (1H, s), 7.46 (1H, s), 7.52 (1H, d, J = 8.7 Hz), 7.59 (1H, d, J = 8.7 Hz), 7 , 83 (1H, s), 8.05 (1H, s). Example 500 (S) -1- {4 - [(5-chlorobenzofuran) -2-ylmethylene) amino] piperazin-1-yl} -3- (2-chloro-4nitroimidazol-1-yl) -2-methylpropan-2 -ol [3050] ¹ H NMR (CDCb) δ ppm:

[3051] 1.18 (3H, s), 2.42 (1H, d, J = 14.0 Hz), 2.57 (1H, d, J = 14.0 Hz), 2.71 -3, 00 (4H, m), 3.17 (1H, s), 3.23-3.38 (4H, m), 4.02 (2H, s), 6.71 (1H, s), 7.22 (1H, dd, J = 2.1 Hz, 8.7 Hz), 7.33-7.43 (2H, m), 7.50 (1H, d, J = 2.1 Hz), 8.05 (1H, s).

Example 501

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethylphenylamino) piperazin-1-yl] propan-2-ol [3052] Using (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.610 g, 2.82 mmol) and N- (piperazin-1-yl) -4- trifluoromethylaniline (0.760 g, 3.09 mmol) (S) -1- (2-chloro-4-nitroim idazol-1 -yl) -2-methyl-3- [4- (4trifluoromethylphenylamino) piperazin-1- yl] propan-2-ol (1.125 g, 86% yield) as a colorless solid in the same manner as in Example 496.

[3053] ¹ H NMR (CDCb) δ ppm:

[3054] 1.15 (3H, s), 2.39 (1H, d, J = 14.0 Hz), 2.54 (1H, d, J = 14.0 Hz), 2.60 - 2, 95 (8H, m), 3.25 (1H, s), 3.99 (2H, s), 4.67 (1H, s), 6.90 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 8.04 (1H, s).

Example 502

Preparation of (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1 -yl] -4-trifluoromethylaniline [3055] Using (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [4- (4trifluoromethylphenylamino) piperazin-1-yl] propan-2-ol prepared in Example 501 ( 1.125 g, 2.43 mmol) (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl was obtained ] -4-trifluoromethylaniline (0.715 g, 69% yield) as a white solid in the same manner as in Example 493.

[3056] Melting point 192.1 -195.3 ° C.

Petition 870190039560, of 26/04/2019, p. 717/876

709/854

Example 503

Preparation of (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] ter-butyl carbamate [3057] Using ( S) - {4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazin-1-yl} tert-butyl carbamate prepared in Example 497 (36.68 g) ter-butyl (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1yl] carbamate (19 , 51 g, 58% yield) as a white powder in the same manner as in Example 493.

[3058] Optical purity> 99.5% e.e.

[3059] [oc] d ²⁷ = 9.84 ° (concentration: 1.016, CHCb) [3060] ¹ H NMR (CDCb) δ ppm:

[3061] 1.43 (9H, s), 1.60 (3H, s), 2.35 (1H, d, J = 14.0 Hz), 2.52 - 2.92 (9H, m),

3.89 (1H, d, J = 9.7 Hz), 4.27 (1H, d, J = 9.7 Hz), 5.35 (1H, s), 7.53 (1H, s).

Example 504

Preparation of (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] -N- (4-trifluoromethylbenzylidene) amine [3062] To a mixture of (S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- {4 - [(4trifluoromethylbenzylidene) amino] piperazin-1-yl} propan-2-ol prepared in Example 496 (847 mg, 0.85 mmol) and DMF (4 ml), sodium hydride (69 mg, 1.73 mmol) was added, followed by stirring for 2.5 hours with cooling in an ice bath. Water was added to the reaction mixture, and the precipitates were removed by filtration. The resulting solid was washed with methanol and recrystallized from acetone / water giving (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] N- (4-trifluoromethylbenzylidene) amine (248 mg, 69% yield) as a light yellow powder.

[3063] Melting point 201 -202.3 ° C (decomposition) [3064] Optical purity> 99.5% e.e.

[3065] [oc] d ²⁷ = -64.64 ° (concentration: 1.018, CHCb) [3066] ¹ H NMR (CDCb) δ ppm:

[3067] 1.64 (3H, s), 2.55 - 2.79 (3H, m), 2.80 - 3.20 (7H, m), 3.94 (1H, d, J = 9, 7

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710/854

Hz), 4.33 (1H, d, J = 9.7 Hz), 7.44 (1H, s), 7.48 - 7.67 (5H, m).

[3068] Using corresponding starting materials, compounds of Examples 505 to 507 were obtained in the same manner as in Example 504.

Example 505 (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -N- (4trifluoromethylbenzylidene) amine [3069] Melting point 188.4-191.2 ° C [3070] Optical purity> 99.0% ee

[3071] [a] d ²⁷ = -58.30 ° (concentration: 1.024, CHCb) [3072] ¹ H NMR (CDCb) δ ppm:

[3073] 1.64 (3H, s), 2.55 - 2.77 (3H, m), 2.82 - 3.18 (7H, m), 3.94 (1H, d, J = 9, 7

Hz), 4.33 (1H, d, J = 9.7 Hz), 7.16 (2H, d, J = 8.2 Hz), 7.43 (1H, s), 7.55 (1H, s), 7.58 (2H, d, J = 8.2 Hz).

Example 506 (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -N- (5trifluoromethylbenzofuran- 2-ylmethylene) amine [3074] Melting point 190.2-191.8 ° C [3075] Optical purity 99.8% ee

[3076] [a] d ²⁷ = -81.05 ° (c = 0.992, CHCb) [3077] ¹ H NMR (CDCb) δ ppm:

[3078] 1.64 (3H, s), 2.59 - 2.77 (3H, m), 2.86 - 3.00 (3H, m), 3.05 - 3.26 (4H, m) ,

3.96 (1H, d, J = 9.7 Hz), 4.33 (1H, d, J = 9.7 Hz), 6.79 (1H, s), 7.39 (1H, s), 7.41 - 7.57 (3H, m), 7.82 (1H, s).

Example 507 (S) -N- (5-chlorobenzofuran-2-ylmethylene) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) piperazin- 1-yl] amine [3079] Optical purity> 99.0% ee

[3080] [a] d ²⁷ = -84.48 ° (concentration: 1.018, CHCb) [3081] Melting point 213.8-215.7 ° C [3082] ¹ H NMR (CDCb) δ ppm:

Petition 870190039560, of 26/04/2019, p. 719/876

711/854 [3083] 1.63 (3H, s), 2.57 - 2.76 (3H, m), 2.81 - 2.95 (3H, m), 3.00 - 3.24 (4H , m),

3.94 (1H, d, J = 9.7 Hz), 4.32 (1H, d, J = 9.7 Hz), 6.67 (1H, s), 7.17 - 7.23 (1H , m), 7.30 - 7.43 (2H, m), 7.48 (1H, d, J = 2.1 Hz), 7.53 (s, 1H).

Example 508

Preparation of (S) -N- (5-chlorobenzofuran-2-ylmethylene) -N- [4- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin- 1-yl] amine (alternative synthesis of the compound of Example 507) [3084] A mixture of (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] was added to a mixture oxazol-2-ylmethyl) piperazin-1-yl] ter-butyl carbamate prepared in Example 503 (0.20 g, 0.523 mmol) and 5-chlorobenzofuran-2-carbaldehyde (0.113 g, 0.628 mmol) and methylene chloride ( 4 ml), trifluoroacetic acid (0.4 ml), followed by stirring at room temperature for 2 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 4/1) giving (S) -N- (5-chlorobenzofuran-2-methylene) ) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1yl] amine (0.137 g, 59% yield) as a light yellow powder.

Example 509

Preparation of (S) -N- [1 - (4-chlorophenyl) ethylidene] -N- [4- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin -1-yl] amine [3085] A mixture of (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] tert-butyl carbamate prepared in Example 503 (200 mg, 0.52 mmol), trifluoroacetic acid (2 ml) and methylene chloride (4 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (4 ml) and then neutralized with triethylamine (4 ml, 28.7 mmol). To the neutralized solution, a solution of 4-chloroacetophenone (97 mg, 0.63 mmol) in ethanol (4 ml) was added, followed by stirring at reflux for 4 hours. The reaction mixture was allowed to return to

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712/854 at room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / acetone = 3/1) giving (S) -N- [1- (4-chlorophenyl) ethylidene] -N- [4- (2 -methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] amine (39 mg, 18% yield) as a light yellow powder. [3086] Melting point 164.6-166.5 ° C [3087] Using corresponding starting materials, compounds of Examples 510 to 513 were obtained in the same manner as in Example 509.

Example 510 (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -N- [1 ( 4-trifluoromethylphenyl) ethylidene] amine [3088] Melting point 167.9-169.4 ° C

Example 511 (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -N- [1 ( 4-trifluoromethoxyphenyl) ethylidene] amine [3089] Melting point 177.8-180.1 ° C

Example 512 (S) -N-Cyclohexylidene-N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Imethyl) piperazin-1-yl] amine [3090] Melting point 178.6-179.3 ° C

Example 513

N- (2-Benzylideneeptylidene) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Imethyl) piperazin-1-yl] amine [3091] Melting point 166.6-169.6 ° C.

Example 514

Preparation of (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] -N- (4-trifluoromethylbenzyl) amine [3092] To a mixture of (S) -N- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole-

2-ylmethyl) piperazin-1-yl] -N- (4-trifluoromethylbenzylidene) amine prepared in Example 504 (100 mg, 0.23 mmol) and THF (4 ml), sodium borohydride (13 mg, 0 , 34 mmol) with cooling in an ice bath, followed by stirring at room temperature

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713/854 room for 30 minutes. Methanol (1 ml) was added to the reaction mixture, and the solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 2/1) giving (S) -N [4- (2-methyl-6-nitro-2,3-dihydroimidazo) [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] -N- (4trifluoromethyl benzyl) amine (32 mg, 31% yield) as a light yellow powder. [3093] Melting point 131.3-135.5 ° C.

Example 515

Preparation of (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Imethyl) piperazin-1-yl] amine dihydrochloride [3094] of ter (butyl) [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] carbamate prepared in Example 503 (300 mg, 0.78 mmol), concentrated hydrochloric acid (2 ml) and methanol (4 ml) was stirred at 50 ° C for 30 minutes. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The residue was recrystallized from methanol / ether giving (S) - [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] amine dihydrochloride (265 mg, 91% yield) as a yellow powder.

[3095] Melting point 176 ° C (decomposition).

Example 516

Preparation of 3- [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] -5- (4trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazole- 2-one [3096] To a suspension of 2-chloro-4-nitro-1 H-imidazole (2.21 g, 14.98 mmol) and 3 (2-methyloxyran-2-ylmethyl) -5- (4- trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazol-2-one (2.37 g, 7.49 mmol) in ethanol (25 ml), sodium hydrogen carbonate (1.32 g, 15.73 mmol), followed by stirring at reflux for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, and concentrated under reduced pressure giving 3 [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] -5- (4-trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazol-2-one (3.27 g, 94% yield) as a light yellow amorphous form.

[3097] ¹ H NMR (DMSO-de) δ ppm:

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714/854 [3098] 1.53 (3H, s), 3.67 (1H, d, J = 8.8 Hz), 3.81 (1H, d, J = 8.8 Hz), 4.49 (2H, s),

7.42-7.66 (2H, m), 7.86-8.09 (2H, m), 8.54 (1H, s), 10.98 (1H, br).

[3099] Using corresponding starting materials, compounds of Examples 517 to 523 shown in the following table were obtained in the same manner as in Example 516.

Table 18

R

Example R Ή NMR 5 Rend. (¾) 517 CBClj 1.59C3H, s), 3.78 (111, d, 3.86 (1H, d, J-8.5Hz), 4.29ÜH, d, J = 15.1Hz), 4.57 (1H, d, 7.61Í2H, d, J ^ S.lHz), 7.79 (2H, d, J = 8.1 Hz), 8.06 H1, e), 9.17 H1, br). 70 518 - ^ 5 ^ 0 CDClj 1.61C3H, s), 3.79 (1H, d, J = 8.5Hz), 3.85 (1H, d, J-8.5Hz), 4.27 (1H, d, J = 15.0Hz), 4.56Í1H, d, J = 15.0Hz ), 7.33-7.63 (7H, τη), 7.78Í2H, d, j = e.4Hz), e.oedH, _s ), s, 02 (ih, br). 82 51S CDClj 1.62 (311 s). 3.75Í1H, d, JB.BHz), 3.83ÜH, d, J = 8.5Hz), 4.27 (111, d, J = 15.0Hz), 4.B4Í1H, d. J-15.0Hz), 7.34 (2H, dd, J-1.8Hz, 8.6Hz), 7.Ê3Í2H, dd _f J ^ l.SHz, 8.6Hz), 8.D3 (1H, s), 9.05Ϊ1Η, en ). 57 520 * DMSO- 1.51Í3H, ê), 3.66Í1H, d, J = 8.SHz), 3.79 (1H. D, J = 8.SHz), 4.4BÍ2H, s), 7.24'7.41 (211, m), 7.84 '7.96Í2H , m), 8.52 H, s). 64 521 CD01, 1.56Ϊ8Η, s). 2.41-2.53Í2H, m), 2.81-3.00Í2H, m), 3.56 (1H, d, J = 8.6Hz), 3.63Í1H, d, J = 8-5Hz), 4.22Í1H, d, J = 15.0 Hz), 4 42 <1Η, d, J = 15.0Hz), 7.12 (2H, d, J = 8.4Hz), 7.26 (2H, d, J-8.4Hz), 7.55 (111.br), 7.97Ϊ1Η. s). 92 522 DMSOd ₍ 1.53 (3H, s), 3.63Í1H, d, J = 8.BHz), 3.77Ϊ1Η, d, J = 8.8Hz), 4.43Ϊ1Η, d, J 15.0Hz), 4.5i (lH, d, J = 15.0) Hz), 6.58 × 1K d, J = 15.9 Hz), 7.43-7.55 × 3H. m), 7.64 (2H, d, J -8.5Hz). 7.51, 1H, s). E9 528 CD Cl] 1.56 (3H, s), 3.72 (211, s), 4.25Í1H, d, 15.1Hz), 4.44 (1H, d, Jl 5.1Hz), 4.59Í2H, s}, 6.85 (2H _t dd, J = 2.3Hz , 6.8Hz), 7.29 (2H, dd, J ~ 2.3Hz 6.8Hz), 7. & 8 (1H, a), 8.49 (1H, br). 98

Example 524

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715/854 [3100] Preparation of 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 5- (4-trifluoromethoxyphenyl) -3H- [1, 3.4] oxadiazol-2-one [3101] To a solution of 3- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] 5- (4-trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazol-2-one prepared in Example 516 (3.27 g, 7.05 mmol) in 1,4-dioxane (70 ml), sodium hydride (0, 37 g, 9.17 mmol) with cooling in an ice bath, followed by stirring at reflux for 3 hours. The reaction mixture was concentrated under reduced pressure. Water with ice bath cooling was added to the solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (methylene chloride / ethyl acetate = 4/1) and recrystallized from acetonitrile ethanol giving 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2 , 1-b] oxazol-2-ylmethyl) -5- (4trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazol-2-one (1.43 g, 48% yield) as a white solid.

[3102] Melting point 190-191 ° C.

[3103] Using corresponding starting materials, compounds of Examples 525 to 531 were obtained in the same manner as in Example 524.

Example 525

3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- (4-trifluoromethylphenyl) -3H- [1,3,4] oxadiazole-2 -one [3104] Melting point 230-231 ° C.

Example 526 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- (biphenyl-4-yl) -3H- [1,3,4 ] oxadiazol-2-one [3105] Melting point 248-249 ° C.

Example 527 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- (4-chlorophenyl) -3H- [1,3,4] oxadiazole -2-one [3106] Melting point 221-222 ° C.

Example 528

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716/854

3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl) -5- (4-fluorophenyl) -3H- [1,3,4] oxadiazole-2 -one [3107] Melting point 188-191 ° C.

Example 529

3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- [2- (4-chlorophenyl) vinyl] -3H- [1,3, 4] oxadiazole-2-one [3108] Melting point 249-252 ° C.

Example 530

3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- [2- (4-chlorophenyl) ethyl] -3H- [1,3, 4] oxadiazole-2-one [3109] Melting point 139-140 ° C.

Example 531

3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- (4-chlorophenoxymethyl) -3H- [1,3,4] oxadiazole-2 -one [3110] Melting point 64-66 ° C.

Example 532

Preparation of 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5-phenyl-3H- [1,3,4] oxadiazole-2-one [3111] A mixture of 2-chloro-4-nitro-1 H-imidazole (170 mg, 1.15 mmol), 3- (2-methyloxyran-2-ylmethyl) -5-phenyl-3H- [1,3,4 ] oxadiazol-2-one (310 mg, 0.9 mmol), sodium hydrogen carbonate (120 mg, 1.43 mmol) and ethanol (2 ml) was stirred at reflux for 2.5 hours. The reaction mixture was allowed to return to room temperature, then diluted with water. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, the residue was dissolved in 1,4-dioxane (10 ml). Sodium hydride (55 mg, 1.38 mmol) was added to the solution, followed by stirring at room temperature for 1 hour and then stirring at reflux for 1.5 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under

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717/854 reduced pressure, and the residue was recrystallized from ethanol giving 3- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5-phenyl-3H- [1 , 3.4] oxadiazole-2-one (127 mg, 32% yield) as a light brown powder.

[3112] Melting point 225-227 ° C.

Example 533

Preparation of 5- (4-chlorobenzyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) -3H- [1,3,4] oxadiazole-2 -one [3113] A mixture of 2-methyloxyran-2-ylmethyl 4-methylbenzenesulfonate (3.98 g, 18.9 mmol), 5- (4-chlorobenzyl) -3H- [1,3,4] oxadiazole- 2-one (5.5 g, 26.11 mmol), potassium carbonate (3.4 g, 24.6 mmol), sodium iodide (3.4 g, 22.68 mmol) and DMF (40 ml) it was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washing with water three times, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give a yellow oil (5.47 g).

[3114] A mixture of 2.3 g of yellow oil (11.02 mmol), 2,4-dinitro-1 Himidazole (2.26 g, 14.3 mmol), sodium acetate (1.81 g, 22 , 07 mmol) and ethanol (22 ml) was stirred at reflux for 8 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 3/1) giving 5- (4-chlorobenzyl) -3- (2- methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -3H- [1,3,4] oxadiazol-2-one (240 mg, 9%) as a white solid .

[3115] Melting point 151-153 ° C.

Example 534

Preparation of 5- (4-bromophenyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) -3H- [1,3,4] oxadiazole-2 -one [3116] A mixture of 2-methyl-6-nitro-2,3-dihydroimidazo methanesulfonate [2,1

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718/854

b] oxazol-2-ylmethyl prepared in Example 41 (1.02 g, 3.67 mmol), 5- (4-bromophenyl) 3H- [1,3,4] oxadiazol-2-one (680 mg, 2, 82 mmol), potassium carbonate (580 mg, 4.2 mmol), sodium iodide (890 mg, 5.94 mmol) and DMF (15 ml) was stirred at 100 ° C for 3 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water three times, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1) giving 5- (4-bromophenyl) -3- (2- methyl-6-nitro2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -3H- [1,3,4] oxadiazol-2-one (17.4 mg, 2% yield) as a light yellow powder.

[3117] Melting point 231 -233 ° C.

Example 535

Preparation of 5- (4-bromophenyl) -3- (6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 3H- [1,3,4] oxadiazole-2-one [ 3118] Using 6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl methanesulfonate prepared in Example 40 (3.28 g, 12.46 mmol) and 5- (4-bromophenyl) -3H- [1,3,4] oxadiazol-2-one (1.5 g, 6.22 mmol) 5- (4-bromophenyl) -3- (6-nitro-2,3dihydroimidazo [2,1-b ] oxazol-2-ylmethyl) -3H- [1,3,4] oxadiazol-2-one (312 mg, 12% yield) as a light brown powder in the same manner as in Example 534. [3119] Melting point 264 ° C (decomposition).

[3120] Using corresponding starting materials, the compound of Example 536 was obtained in the same way as in Example 535.

Example 536

3- (6-Nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- (4-trifluoromethoxy phenyl) -3H- [1,3,4] oxadiazol-2-one [ 3121] Melting point 204-207 ° C.

Example 537

Preparation of 3- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-yl) ethyl] -5- (pyridin-

4- yl) -3H- [1,3,4] oxadiazole-2-one

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719/854 [3122] A mixture of 5- (pyridin-4-yl) -3H- [1,3,4] oxadiazol-2-one (150 mg, 0.92 mmol), sodium hydride (41 mg, 1.03 mmol) and DMF (1.5 ml) was stirred at room temperature for 1 hour. To the reaction mixture, 2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl methanesulfonate prepared in Example 42 (200 mg, 0.69 mmol) was added and sodium iodide (140 mg, 0.93 mmol) in that order, followed by stirring at 50-60 ° C for 6 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water three times, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 25/1) giving 3- [2- (2-methyl-6-nitro) -2,3-dihydroimidazo [2,1 -b] oxazol-2-yl) ethyl] -5- (pyridin-4yl) -3H- [1,3,4] oxadiazol-2-one (137 mg, yield 56%) as a white powder.

[3123] Melting point 147-149 ° C.

[3124] Using corresponding starting materials, the compound of Example 538 was obtained in the same manner as in Example 537.

Example 538 3- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl] -5- (pyrazin-2-yl) -3H- [ 1.3.4] oxadiazole-2-one [3125] Melting point 209-212 ° C.

Example 539

Preparation of (R) -3- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] -5- (4trifluoromethoxyphenyl) -3H- [1,3, 4] oxadiazol-2-one [3126] To a solution of 5- (4-trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazol-2-one (0.68 g, 2.76 mmol) and (R ) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (0.50 g, 2.30 mmol) in DMF (5 ml), potassium carbonate ( 0.38 g, 2.76 mmol), followed by stirring at room temperature for 16 hours, and then water was added. The solution was extracted with ethyl acetate, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (chloride

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720/854 methylene / ethyl acetate = 4/1) giving (R) -3- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy2-methylpropyl] -5- (4-trifluoromethoxyphenyl ) -3H- [1,3,4] oxadiazole-2-one (1.06 g, quantitative yield) as a white amorphous form.

[3127] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3128] 1.53 (3H, s), 3.67 (1H, d, J = 8.8 Hz), 3.81 (1H, d, J = 8.8 Hz), 4.49 (2H, s),

7.42-7.66 (2H, m), 7.86-8.09 (2H, m), 8.54 (1H, s), 10.98 (1H, br).

Example 540

Preparation of (R) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- (4trifluoromethoxyphenyl) -3H- [1,3,4 ] oxadiazol-2-one [3129] To a solution of (R) -3- [3- (2-chloro-4-nitroim idazol-1 -yl) -2-hydroxy-2methylpropyl] -5- (4-trifluoromethoxyphenyl ) -3H- [1,3,4] oxadiazol-2-one prepared in Example 539 (0.87 g, 1.88 mmol) in 1,4-dioxane (18 ml), sodium hydride (98 mg, 2.44 mmol) with cooling in an ice bath. The mixture was stirred at reflux for 5 hours, concentrated under reduced pressure, then water was added with cooling in an ice bath. The solution was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 9/1), and recrystallized from acetonitrile / isopropanol giving (R) -3- (2-methyl-6-nitro- 2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5- (4trifluoromethoxyphenyl) -3H- [1,3,4] oxadiazol-2-one (0.32 g, 40% yield) like a white powder.

[3130] Optical purity 98.2% e.e.

[3131] [oc] d ²⁶ = -12.43 ° (concentration: 0.668, CHCb) [3132] Melting point 146-148 ° C.

Example 541

Preparation of 3- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] -3Hbenzoxazol-2-one [3133] To a suspension of 2-chloro-4 -nitro-1 H-imidazole (503 mg, 3.41 mmol), 3 (2-methyloxyran-2-ylmethyl) -3H-benzoxazol-2-one (700 mg, 3.41 mmol) in ethanol (7 ml) , sodium acetate (336 mg, 4.1 mmol) was added, followed by reflux stirring

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721/854 for 8 hours. The reaction mixture was allowed to return to room temperature. Water was added to the mixture, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 30/1) giving 3 [3- (2-chloro-4-nitroimidazole-1- il) -2-hydroxy-2-methylpropyl] -3H-benzoxazol-2-one (616 mg, 51% yield) as a light yellow powder.

[3134] ¹ H NMR (CDCb) δ ppm:

[3135] 1.31 (3H, s), 3.04 (1H, s), 3.87 (1H, d, J = 14.7 Hz), 3.98 (1H, d, J = 14.7

Hz), 4.13 (1H, d, J = 12.5 Hz), 4.24 (1H, d, J = 14.5 Hz), 7.08-7.31 (4H, m), 8, 04 (1H, s).

[3136] Using corresponding starting materials, compounds of Examples 542 and 543 shown in the following table were obtained, in the same manner as in Example 541.

Example R Ή NMR <5 Rend. (¾) 542 Cl CDClj 1.32Í3H, b), 3.14C1H, s), 3.87 (1H, d, J = 14.7Hz), 3.95 (1H, d, J = 14.7Hz), 4.11Í1H, d, J = 14.4Hz), 4.25 (1H , d, J = 14.4 Hz), 7.10'7.23 (3H, m), 8.Q3I1H, s). 35 543 F CDCl _â L11 (3H, b), 2.66 (1H, s), 3.86 (1H, d, J = 14.5Hz), 3.94 (1H, d, J = 14.6Hz), 4.16 (1H, d, J = 14.3Hz), 4.24Í1H, d, J-14.3Hz), 6.89-7.O0Í1H, iu), 7.29 (1H, dd, J — 2.7Hz, 8.8Ha), 7; 37Í1H, dd, J = 4.4Hz, 8.8Hz), 8.01 (1H, 6). 33

Example 544 [3137] Preparation of 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 3H-benzoxazol-2-one

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722/854 [3138] A mixture of 3- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] 3H-benzoxazol-2-one prepared in Example 541 (615 mg , 1.74 mmol), sodium hydride (76.6 mg, 1.91 mmol), 1,4-dioxane (15 ml) was stirred at reflux for 1 hour. The reaction mixture was allowed to return to room temperature. Water was added to the solution and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 30/1) giving 3- (2-methyl-6-nitro-2,3- dihydroimidazo [2,1b] oxazol-2-ylmethyl) -3H-benzoxazol-2-one (209 mg, 38% yield) as a white powder.

[3139] Melting point 222.7-224.3 ° C.

[3140] Using corresponding starting materials, compounds of Examples 545 and 546 were obtained in the same manner as in Example 544.

Example 545

5-chloro-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -3H-benzoxazol-2ona [3141] Melting point 207.6-207 , 9 ° C.

Example 546 5-Fluoro-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -3H-benzoxazol-2ona [3142] Melting point 246.2 -246.8 ° C.

Example 547

Preparation of 5-bromo-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) 3H-benzoxazol-2-one [3143] A mixture of 2- chloro-4-nitro-1 H-imidazole (3.22 g, 21.8 mmol), 5-bromo3- (2-methyloxyran-2-ylmethyl) -3H-benzoxazol-2-one (6.2 g, 21 , 8 mmol), sodium acetate (1.97 g, 24 mmol) and ethanol (50 ml) was stirred at reflux for 8 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then

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723/854 filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (60 ml). Sodium hydride (528 mg, 13.21 mmol) was added to the solution, followed by stirring at 70-80 ° C for 17 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, which was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 30/1) giving 5-bromo-3- (2-methyl-6-nitro- 2,3 dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -3H-benzoxazol-2-one (1.82 g, 37% yield) as a white powder.

[3144] Melting point 243-245.5 ° C.

Example 548

Preparation of 5- (2-chloro-4-nitroimidazole-1-yl alcohol) -3- (4-hydroxybiphenyl-3-yl) -5methyloxazolidin-2-one [3145] A mixture of 2-chloro-4 -nitro-1 H-imidazole (1.3 g, 8.78 mmol), 5-phenyl-3- (2methyloxyran-2-ylmethyl) -3H-benzoxazol-2-one (2.47 g, 8.78 mmol ), sodium acetate (792 mg, 9.66 mmol) and ethanol (30 ml) was stirred at reflux for 10 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) giving 5- (2-chloro-4-nitroimidazole-1-ylmethyl) -3- (4-hydroxybiphenyl-3-yl) -5-methyloxazolidin-2one (1.82 g, 61% yield) as a white powder.

[3146] ¹ H NMR (DMSO-de) δ ppm:

[3147] 1.55 (3H, s), 3.85 (1H, d, J = 9.5 Hz), 3.98 (1H, d, J = 9.5 Hz), 4.46 (1H, d,

J = 14.9 Hz), 4.56 (1H, d, J = 14.9 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.27 (1H, t, J = 7.3 Hz), 7.36-7.57 (6H, m), 8.52 (1H, s), 10.06 (1H, s).

Example 549

Preparation of 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5-phenyl-3H

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724/854 benzoxazol-2-one [3148] A mixture of 5- (2-chloro-4-nitroimidazol-1-ylmethyl) -3- (4-hydroxybiphenyl-3-yl) 5-methyloxazolidin-2-one prepared in Example 548 (1.23 g, 2.88 mmol), sodium hydride (127 mg, 3.16 mmol) and DMF (10 ml) was stirred at 100 ° C for 4 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride. The organic phase was washed with water and a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving 3- (2-methyl-6-nitro-2,3dihydroimidazo [ 2,1-b] oxazol-2-ylmethyl) -5-phenyl-3H-benzoxazol-2-one (172 mg, 15% yield) as a yellowish brown powder.

[3149] Melting point 254-254.6 ° C.

Example 550

Preparation of 3- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl] -3Hbenzoxazol-2-one [3150] A mixture of 2- benzoxazolinone (240 mg, 1.8 mmol), sodium hydride (67 mg, 1.95 mmol) and DMF (10 ml) was stirred at room temperature for 30 minutes. 2- (2-methyl-6-nitro-methanesulfonate) was added to the reaction mixture

2.3- dihydroimidazo [2,1-b] oxazol-2-yl) ethyl prepared in Example 42 (500 mg, 1.7 mmol), followed by stirring at 50-60 ° C for 4 hours. The reaction mixture was allowed to return to room temperature and poured into ice water. The precipitates were removed by filtration and recrystallized from ethanol giving 3- [2- (2-methyl-6-nitro-

2.3- dihydroimidazo [2,1-b] oxazol-2-yl) ethyl] -3H-benzoxazol-2-one (320 mg, 56% yield) as a light brown powder.

[3151] Melting point 193-195 ° C.

Example 551

Preparation of 3- [5- (2-chloro-4-nitroim idazol-1-yl) -4-hydroxy-4-methyl Ipenti] -3Hbenzoxazol-2-one [3152] Using 3- [3- (2- methyloxyran-2-yl) propyl] -3H-benzoxazol-2-one (3.8 g, 16.3

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725/854 mmol) 3- [5- (2-chloro-4-nitroimidazole-1-yl) -4-hydroxy-4-methyl ethyl]] -3Hbenzoxazol-2-one (3.5 g, 68 %) as a white powder in the same way as in Example 541.

[3153] ¹ H NMR (CDCb) δ ppm:

[3154] 1.20 (3H, s), 1.49 - 1.70 (2H, m), 1.88 - 2.07 (2H, m), 2.68 (1H, s), 3.81 3.93 (2H, m), 4.00 (2H, s), 6.98 (1H, d, J = 7.3 Hz), 7.09 - 7.26 (3H, m), 8.00 (1H, s). Example 552

Preparation of 3- [6- (2-chloro-4-nitroimidazol-1-yl) -5-hydroxy-5-methylexyl] -3H-benzoxazol2-one [3155] Using 3- [4- (2-methyloxyran-2 -yl) butyl] -3H-benzoxazol-2-one (1.2 g, 4.86 mmol) 3- [6- (2-chloro-4-nitroimidazol-1-yl) -5-hydroxy- 5-methylexyl] -3H benzoxazol-2-one (1.2 g, 62%) as a white powder in the same manner as in Example 541.

[3156] ¹ H NMR (CDCb) δ ppm:

[3157] 1.16 (3H, s), 1.38 -1.58 (4H, m), 1.67 -1.86 (2H, m), 2.15 (1H, s), 3.87 (2H, t, J = 6.6 Hz), 3.98 (2H, s), 6.98 (1H, d, J = 7.8 Hz), 7.08 - 7.26 (3H, m) , 8.01 (1H, s). Example 553

Preparation of 3- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl] -3Hbenzoxazol-2-one [3158] Using 3- [5 - (2-chloro-4-nitroimidazol-1-yl) -4-hydroxy-4-methylpentyl] -3Hbenzoxazol-2-one prepared in Example 551 (3.5 g, 9.2 mmol) 3- [ 3- (2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl] -3H-benzoxazol-2-one (2.4 g, 76% yield) as a light yellow powder in the same way as in Example 544.

[3159] Melting point 180-181 ° C.

Example 554

Preparation of 3- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) butyl] -3Hbenzoxazol-2-one [3160] Using 3- [6 - (2-chloro-4-nitroimidazol-1-yl) -5-hydroxy-5-methylexyl] -3Hbenzoxazol-2-one prepared in Example 552 (1.2 g, 3 mmol) 3- [4- (2-methylPetition 870190039560, of 26/04/2019, page 734/876

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6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) butyl] -3H-benzoxazol-2-one (780 mg, 72% yield) as a light yellow powder in the same way as in Example 544.

[3161] Melting point 155-158 ° C.

Example 555

Preparation of 1- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] -3-methyl-1,3dihydrobenzimidazole-2-one [3162] Using 1-methyl-3 - (2-methyloxyran-2-ylmethyl) -1,3-dihydrobenzimidazole-2-one (1.41 g, 6.46 mmol) 1- [3- (2-chloro-4-nitroimidazole-1-) il) -2-hydroxy-2methylpropyl] -3-methyl-1,3-dihydrobenzimidazole-2-one (1.23 g, 63% yield) as a white powder in the same manner as in Example 541.

[3163] ¹ H NMR (CDCb) δ ppm:

[3164] 1.23 (3H, s), 3.47 (3H, s), 3.94 (1H, d, J = 12.4 Hz), 4.03 (1H, d, J = 12.4

Hz), 4.06 (1H, d, J = 11.9 Hz), 4.17 (1H, d, J = 11.9 Hz), 4.79 (1H, s), 7.00-7, 21 (4H, m), 8.09 (1H, s).

[3165] Using corresponding starting materials, compounds of Examples 556 to 565 shown in the following table were obtained in the same manner as in Example 555.

Table 20

«5

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Example R R ’ Ή NMR â Rend. {*} 556 H 1.23Í3H, b), 1.51Í9H, a), 1.75-1.89Í2H, m), 2.17Í2H, b), 2.20-2.4IÍ2H, m), 2.75-2.91Í2H, m), 3.90Í1H, d, J = 14.2 Hz), 4.16 (1H, d, J = 14.2Hz), 4.25-4.50 (3H, m), 7.00'7.23 (4H, m), 8.09Í1H. s). 78 557 Me 6-C1 1.24 (3H, b), 3.45 (3Ή, b), 3.94 ± 2H, (i), 4.06 ± 1H, d, J = 14.4 Hz), 4.18 ± 1H. d, J-14.4Hz), 6.96 (1H, d, J0.4Hz), 7.06 (1H, d, J = 1.9Hx), 7.16 (IH _f dd, J = 1.9 Hz. 8.4 Hz). 8.O8C1H, a) 69 558 Me 6-CFj 1.26Ϊ3Η, e), 3.51 (311. E), 3.95 (1H, d, J ^ S.SHz), 4.03 (1H, d, J = 8.5Hz), 4.14Í1H, d, J = 14.3Hz) , 4.21 (111, d, J = 14.3Hz), 7.13 (1Η, d, J = 8.3Hz). 7.3.1 (IH., 6). 7.48 (1H, d, J = 8.3Hz), 8.07 ± 1H, s). 61 559 Me 5-CJ 1.23Í3H, e), 3.47 (3H, a), 3.91Ϊ1Η, d, J = 14.8Hz), 3.99 (1H, d, J = 14.8Hz), 4.05 (1H, d, J = 14.0Hz), 4.17Í1H , d, J-14.0Hz), 6.97 (1H, d, J = 8.4Hz), 7.06 (1H, d, J = 1.9Hz), 7.14 (1H), dd. J-1.9IL ·, 8.4Hz), 8.07 (lH _t a). 86 560 Me 6-F 1.24 (3H, s), 3.46Í3H, s), 3.90Í1H, d _r J = 14.8Hz), 3.97 (1H, d, J-14.8Hz), 4.O6Í1H, d, J = 14.3Hz), 4.17Í1H , d, 3 = 14.3Hz), 6.79'7.00 (3H, m), 8.08 (111, b). 68 561 Et 6-C1 1.21 (33, a). 1.36 (3H, t, J = 7.2Hz), 3.84 * 4.20 (6H, m), 8.98 (111, d, J = 8.4Hz) _f 7.06Í1H, d, J = L8Hz), 7.15 (1H, dd, J -1.8Hz, 8.4Hz), 8.08Ϊ1Η, s). 77 £ 62 isopropyl 6 * Cl 1.24OH, s). l.ÜBÍBH, d, J = 7.0Hz), 3.93 (2H, e), 4.06 (1H, d, J = 14.3Hz), 4.17ÜH, d, J = 14.3Hz), 4.55-4.75 (1H, m) , 7.05 ± 1H. The). 7.18Í2H, b), 8.09Í1H, b). 69 563 Me 6 * NMe _: 1.23OH, a), 2.96 (6H, b), 3.42 (3H, b), 3.89 (1H, d, J = 14.8Hz), 3.99 H1, d, J = 14.B Hz), 4.05 H1 d, J = 14.3 Hz), 4.16ÜH, d, J = 14.3Hz), 6.39Í1H, d, 2.2Hz), 6.60Í1H, dd, J = 2.2Hz, 8.6Hz), 6.92 (1H, d, J = 8.6Hz ), 8.101-1H, a). Crude 564 n * hexyl 6-C1 0.87 (3H, t, J = 6.9Hz), 1.16Ί.39 (9Η, m), 1.64 1.82 (2H. M), 3.80-8.93 (4H, m), 4.0BÍ1H, d, tJ = 14.3Hz), 4.17C1H, d, J = 14.3Hz), 6.97 (1H, d, J = 8.4Hz), 7.06 (1H, d, J = 1.8Hz), 7.14Í1H. dd, J = 1.8Hz, S.4Hz), 8.08 (1H. s). 55 565 Me 6-CO 0 ₃ Et 1.25 (3H. 4), 1.42 (3H, t, J = 7.1Hz), 3.50 (3H, e). 3.93 * 4.11 (3H, Bl), 4.20 (1H, d, J = 14.3Hz), 4.40 (2H, q. 7.07 (1H, d, J = S.3Hz), 7.75 (1H, d, J = 1.5Hz ), 7.94 (1H, dd, J = l.fiHz, 8.3Hz), 8.07 (lH _f 3), 48

Example 566 [3166] Preparation of 1-methyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) -1,3-dihydrobenzimidazole-2-one

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728/854 [3167] Using 1 - [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl] -3-methyl-

1,3-dihydrobenzimidazole-2-one prepared in Example 555 (1.23 g, 3.37 mmol) gave 1methyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one (563 mg, 51% yield) as a white powder in the same manner as in Example 544.

[3168] Melting point 203.2-204.4 ° C.

[3169] Using corresponding starting materials, compounds of Examples 567 to 576 were obtained in the same manner as in Example 566.

Example 567

1- (1-Ter-butoxycarbonylpiperidin-4-yl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole-

2-ylmethyl) -1,3-dihydrobenzimidazole-2-one [3170] Melting point 218-219.1 ° C.

Example 568

5- chloro-1-methyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one [3171] melting 261.9-265.4 ° C (decomposition).

Example 569 1-methyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -5-trifluoromethyl-1,3dihydrobenzimidazole-2-one [3172] Melting point 232.4-234.7 ° C.

Example 570

6- chloro-1-methyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one [3173] melting 261.3-263.3 ° C.

Example 571 5-Fluoro-1-methyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one [3174] Melting point 244.2-249.8 ° C (decomposition).

Example 572

5-chloro-1-ethyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3Petition 870190039560, of 26/04/2019, p. 737/876

729/854 dihydrobenzimidazole-2-one [3175] Melting point 240.9-245.6 ° C.

Example 573

5-chloro-1-isopropyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one [3176] melting 240.5-244.8 ° C.

Example 574

5-dimethylamino-1-methyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one [3177] melting 264.6-268.3 ° C (decomposition).

Example 575

5-chloro-1- (n-hexyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one [ 3178] Melting point 168.1 -169.3 ° C.

Example 576

5-Ethoxycarbonyl-1-methyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one [3179] melting 265.8-266.7 ° C.

Example 577

Preparation of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -3-phenyl-1,3dihydrobenzimidazole-2-one [3180] Using 1- ( 2-methyloxyran-2-ylmethyl) -3-phenyl-1,3-dihydrobenzimidazole-2-one (758 mg, 2.7 mmol) 1- (2-methyl-6-nitro-2,3-dihydroimidazo) was obtained [2,1-b] oxazol-2ylmethyl) -3-phenyl-1,3-dihydrobenzimidazole-2-one (70 mg, 13% yield) as a white powder in the same manner as in Example 200.

[3181] Melting point 234.5-234.7 ° C.

[3182] Using corresponding starting materials, the compound of Example 578 was obtained in the same manner as in Example 577.

Example 578

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- (4-Fluorophenyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl) -1,3dihydrobenzimidazole-2-one [3183] melting 254.1 -254.7 ° C.

Example 579

Preparation of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) - (3-piperidin4-yl) -1,3-dihydrobenzimidazole-2-one [ 3184] A mixture of 1- (1-ter-butoxycarbonylpiperidin-4-yl) -3- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3 -dihydrobenzimidazole-2-one prepared in Example 567 (371 mg, 0.74 mmol), trifluoroacetic acid (1 ml) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Saturated sodium hydrogen carbonate solution was added to the residue, and the precipitates were removed by filtration. The precipitates were washed with water several times giving 1- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) - (3-piperidin-4-yl) -1, 3-dihydrobenzimidazole-2-one (255 mg, 86% yield) as a light yellow powder.

[3185] Melting point 192.3-198.8 ° C (decomposition).

Example 580

Preparation of 4- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2-oxo-

Benzyl 2,3-dihydrobenzimidazole-1-yl] piperidine-1-carboxylate [3186] To a mixture of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl ) - (3-piperidin-4-yl) -1,3-dihydrobenzimidazole-2-one prepared in Example 579 (90 mg, 0.23 mmol) and methylene chloride (5 ml), triethylamine (75 mg, 0, 74 mmol) and benzyl chloroformate (126 mg, 0.74 mmol) were added in that order with cooling in an ice bath, followed by stirring at room temperature for 3 hours. The reaction mixture was washed with water, a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / acetone = 1/1) giving 4- [3- (2-methyl-6-nitro-2 , Benzyl 3-dihydroimidazo [2,1-b] oxazol-2-methyl) -2-oxo-2,3-dihydrobenzimidazol-1-yl] piperidine-1-carboxylate (25 mg,

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[3187] Melting point 181.7-184.6 ° C.

Example 581

Preparation of 1-benzyl-3- [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2methylpropyl] imidazolidin-2-one [3188] Using 1-benzyl-3- (2 -methyloxyran-2-ylmethyl) imidazolidin-2-one (680 mg, 2.76 mmol) 1-benzyl-3- [3- (2-chloro-4-nitroim idazol-1-yl) -2- hydroxy-2-methylpropyl] imidazolidin-2-one (580 mg, 59% yield) as a white powder in the same manner as in Example 541.

[3189] ¹ H NMR (CDCb) δ ppm:

[3190] 1.18 (3H, s), 3.17 - 3.54 (6H, m), 4.07 (2H, s), 4.37 (2H, s), 7.17-7.40 (5H,

m), 8.13 (1H, s).

[3191] Using corresponding starting materials, compounds of Examples 582 to 587 shown in the following table were obtained in the same manner as in Example 581.

Table 21

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Example R (solvent) Ή NMR d Rend. (%) 582 CD Cl, 1.19 (311. S), 3.16-3.52 (6 «, m}, 4.0SÍ2H, ¢), 4.33 (2«, a), 6.93-7.09 (2 «, m), 7.18-7.30 (2«, m), 8.18 (1 «, ¢), 43 583 CD Cl, 1.19 (311, s), 3.16-3.55 (8 «, m), 4.05 (2«, s), 4.31 (2 «, b), 7.14 (2Ή, dd, J = 2.0 «z, 8.6 Hz), 7.46 (211, dd, J = 2.0 Hz, 8.6 Hz), 8.13 (1H, b). 64 584 DMSO-d * 1.03 (3 «, ¢), 3.02-8.27 (4H, m), 3.39 * 3.55 (2«, m), 3.73 (3 «, s), 4.03 (2«, s), 4.29 (2 «, e) , 6.90 (2 «, d, J = 8.6 Hz). 7.17 (2 «, d, J-8.6Hz), 8.48 (1«, s). 69 585 DMSO-di 1.04 (3 «, b), 3.05-3.25 (4«, m), 3.36 * 3.48 (2 «, m), 4.03 (2«, s), 4.22 (2 «, s), 7.28 (2«, d _t J = 8.3H 7.41 (2 «, d, J = 8.3« z). 8.48 (1 «, a). 60 588 CDClj 1.16Í3H, s), 1.59 * 1.84 (4 «, m), 2.00 * 2.18 (2«, jn), 2.89 * 3.02 (2H, m), 3.09-3.50 (8 «, m), 3.61-3.80 (1 «, m), 4.00 (1«, d, J = 14.3Hz), 4.09 (1 «, d. J = 14.S« z), 7.18-7.86 (5 «, tn), 8.12 Gross 587 DMSO-d _fl 1.03 (3 «, s), 3.05-3.23 (4«, m), 3.30 * 3.50 (2 «, m), 3.76 (3«, ε), 3.77Ϊ3Η, s), 4.02 (2 «, s). 4.20 (2 «, s), 6.47 (1H, dd, J = 2.2Hz, 8.3Hz}, 6.56Í1H, d, J = 2.2« z), 7.06ÜH, d, J = 3.3Hz), 8.48 (1H, s). 58

Example 588 [3192] Preparation of 1-benzyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) imidazolidin-2-one [3193] Using 1-benzyl -3- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2methylpropyl] imidazolidin-2-one prepared in Example 581 (580 mg, 1.47 mmol) 1-benzyl- 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) imidazolidin-2one (395 mg, 75% yield) as a white powder in the same way as in Example 544.

[3194] Melting point 180.2-180.9 ° C.

[3195] Using corresponding starting materials, compounds of Examples 589 to 594 were obtained in the same manner as in Example 588.

Example 589

1- (4-Fluorobenzyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) imidazolidin-2-one [3196] Melting point 182,5- 183.3 ° C.

Example 590

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1- (4-Bromobenzyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) imidazolidin-2-one [3197] Melting point 205.7- 208.1 ° C.

Example 591

1- (4-methoxybenzyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) imidazolidin-2-one [3198] Melting point 158.6- 160.5 ° C.

Example 592

1- (4-chlorobenzyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) imidazolidin-2-one [3199] Melting point 208.7- 209.8 ° C.

Example 593

1- (1-Benzylpiperidin-4-yl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) imidazolidin-2-one [3200] ¹ H NMR (CDCb) δ ppm:

[3201] 1.41 -1.72 (7H, m), 1.97 -2.10 (2H, m), 2.88-2.95 (2H, m), 3.08 - 3.30 ( 4H,

m), 3.43-3.70 (4H, m), 3.81 (1H, d, J = 15.0 Hz), 3.91 (1H, d, J = 10.3 Hz), 4, 51 (1H, d, J = 10.3 Hz), 7.13-7.31 (5H, m), 7.47 (1H, s).

Example 594 1- (2,4-dimethoxybenzyl) -3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) imidazolidin-2-one [3202] Melting point 175-175.4 ° C.

Example 595

Preparation of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -3phenylimidazolidin-2-one [3203] Using 1- (2-methyloxyran-2- ilmethyl) -3-phenylimidazolidin-2-one (300 mg, 1.29 mmol) 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) ) -3phenylimidazolidin-2-one (59 mg, 26% yield) as a white powder in the same manner as in Example 200.

[3204] Melting point 194.8-197.4 ° C.

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Example 596

Preparation of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) imidazolidin2-one [3205] A mixture of 1- (2,4-dimethoxybenzyl) - 3- (2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) imidazolidin-2-one prepared in Example 594 (100 mg, 0.24 mmol), trifluoroacetic acid (2 ml) and methylene chloride (2 ml) was stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate solution was added to the reaction mixture for neutralization. The resulting solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether giving 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) imidazolidin-2-one (50 mg, 78% yield) as a white powder.

[3206] Melting point 224.8-229.1 ° C (decomposition).

Example 597

Preparation of 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) oxazolidin-2one [3207] A mixture of 3- (2-methyloxyran-2-ylmethyl ) oxazolidin-2-one (2.87 g, 18.23 mmol), 2-chloro-4-nitro-1 H-imidazole (2.7 g, 18.23 mmol), sodium acetate (1.64 g , 20.05 mmol) and ethanol (30 ml) was stirred at reflux for 10 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Methylene chloride was added to the residue, and the resulting solution was washed with water, a saturated solution of sodium hydrogen carbonate and a saturated saline solution in that order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (50 ml). Sodium hydride (610 mg, 15.25 mmol) was added to the solution, followed by stirring at reflux overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under pressure

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735/854 reduced, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2 , 1b] oxazol-2-ylmethyl) oxazolidin-2-one (1.54 g, 40% yield) as a white powder. [3208] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3209] 1.59 (3H, s), 3.46-3.71 (4H, m), 4.11 -4.30 (4H, m), 8.15 (1H, s).

Example 598

Preparation of 5-azidomethyl-3- [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl] oxazolidin-2-one [3210] A mixture of 2-chloro-4- nitro-1 H-imidazole (350 mg, 2.37 mmol), 5azidomethyl-3- (2-methyloxyran-2-ylmethyl) oxazolidin-2-one (500 mg, 2.37 mmol), sodium acetate (214 mg , 2.61 mmol) and ethanol (5 ml) was stirred at 70 ° C for 8 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/2) giving 5azidomethyl-3- [3- (2-chloro-4 -nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] oxazolidin-2-one (640 mg, 75% yield) as a light yellow oil.

[3211] ¹ H NMR (CDCb) δ ppm:

[3212] 1.23 (3H, s), 3.17 - 3.35 (2H, m), 3.43 - 3.61 (2H, m), 3.67 - 3.84 (2H, m) ,

4.01 - 4.16 (2H, m), 4.68 - 4.81 (1H, m), 8.04 (1H, s).

Example 599

Preparation of 5-azidomethyl-3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) oxazolidin-2-one [3213] 5-Azidomethyl-3- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2methylpropyl] oxazolidin-2-one prepared in Example 598 (1 g, 2.78 mmol) was dissolved in 1,4-dioxane (10 ml ). Sodium hydride (130 mg, 3.25 mmol) was added to the solution, followed by stirring at 80 ° C for 4 hours. The reaction mixture was allowed to return to room temperature and received the addition of water. The resulting solution was concentrated under reduced pressure. Water was added to the residue, and the solution was

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736/854 extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 20/1) giving 5-azidomethyl-3- (2-methyl-6- nitro-2,3dihydroimidazo [2,1-b] oxazol-2-ylmethyl) oxazolidin-2-one (46 mg, 5% yield) as a light brown powder.

[3214] MS 323 (M ⁺ )

Example 600

Preparation of 1- [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl] -1,4dihydrobenzo [d] [1,3] oxazin-2-one [3215] Using 1- (2-methyloxyran-2-ylmethyl) -1,4-dihydrobenzo [d] [1,3] oxazin-2-one (5.13 g, 23.04 mmol) we obtained 1- [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2methylpropyl] -1,4-dihydrobenzo [d] [1,3] oxazin-2-one (1.54 g, 36% yield ) as a light yellow oil in the same way as in Example 541.

[3216] ¹ H NMR (CDCb) δ ppm:

[3217] 1.23 (3H, s), 3.96 (1H, br), 4.04 - 4.20 (4H, m), 5.28 (2H, s), 7.00 - 7.07 (1H,

m), 7.11 - 7.24 (2H, m), 7.30 - 7.43 (1H, m), 8.07 (1H, s).

Example 601

Preparation of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,4 dihydrobenzo [d] [1,3] oxazin-2-one [3218 ] Using 1- [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl] -1,4 dihydrobenzo [d] [1,3] oxazin-2-one prepared in the Example 600 (1.54 g, 4.20 mmol) obtained 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl-1,4 dihydrobenzo [d] [1.3] oxazin-2-one (0.58 g, 42% yield) as a light bronze solid in the same manner as in Example 544.

[3219] Melting point 230-231 ° C.

Example 602

Preparation of 1 - [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] -3,3-difluoro-

1,3-dihydroindol-2-one [3220] Using 3,3-difluoro-1 - (2-methyloxyran-2-ylmethyl) -1,3-dihydroindol-2-one (1,14

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737/854 g, 4.76 mmol) 1- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] -3,3difluoro-1,3-dihydroindol was obtained -2-one (968 mg, 53% yield) as a white powder in the same manner as in Example 541.

[3221] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3222] 1.09 (3H, s), 3.73 (1H, d, J = 14.5 Hz), 3.87 (1H, d, J = 14.5 Hz), 4.13 (1H, d, J = 14.4 Hz), 4.21 (1H, d, J = 14.4 Hz), 5.39 (1H, s), 7.20 - 7.26 (1H, m), 7, 33 - 7.37 (1H, m), 7.57 - 7.64 (1H, m), 7.67 - 7.71, (1H, m).

[3223] Using corresponding starting materials, compounds of Examples 603 and 604 shown in the following table were obtained in the same manner as in Example 602.

Example R NMR (CDCls) <5 603 Me 1.21Í3H, e), 1.38 (6H, s), 3.77 (1H, d, J = 14.8Hz), 3.87 (1H, d, J = 14.8Hz), 4.05 (1Ή, d, J = 14.3Hz), 4.15 (1H, d _t J = 14.3Hz), 6.91ÜH, d, J = 7.7Hz), 7.02-7.31 (3H, m), 8.07Í1H, s). 604 H 1.24 (3H, s \ 3.64 * 2H, s). 3.79Í1H, d, J = 14.3Hz), 3.89Í1H, d, J = 14.8Hz), 4.09 (1H, d _r J = 14.3Hz), 4.19Í1H, d, J = 14.3Hz), 6.93Í1H, d , J = 7.7 Hz), 7.12 H1, d, J = 7.5 Hz), 7.25-7.35 (2H, m), 8.07 H1, s).

Example 605 [3224] Preparation of 3,3-difluoro-1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-ylmethyl) -1,3-dihydroindol-2-one [3225] Using 1 - [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] -3,3difluoro-1,3-dihydroindol-2-one prepared in Example 602 (903 mg, 2.34 mmol) 3,3-difluoro-1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1 was obtained, 3diidroindol-2-one (77 mg, 9% yield) as a white powder in the same manner as in Example 544.

[3226] Melting point 202-206 ° C.

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738/854 [3227] Using corresponding starting materials, the compound of Example 606 was obtained in the same manner as in Example 605.

Example 606

3,3-dimethyl-1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,3-dihydroindole-

2-one [3228] ¹ H NMR (DMSO-de) δ ppm:

[3229] 1.25 (3H, s), 1.37 (3H, s), 1.78 (3H, s), 3.96 (1H, d, J = 15.1 Hz), 4.00 ( 1H, d, J = 10.7 Hz), 4.22 (1H, d, J = 15.1 Hz), 4.57 (1H, d, J = 10.7 Hz), 7.04 - 7, 17 (3H, m), 7.24 - 7.31 (1H, m), 7.44 (1H, s).

Example 607

Preparation of 1- (2-chloro-4-nitroimidazol-1-yl) -4- (1-ethyl-1 H-tetrazol-5-yl) -2-methylbutan2-ol [3230] Using 1-ethyl-5- [2- (2-methyloxyran-2-yl) ethyl] -1 H-tetrazole (1.04 g, 5.59 mmol) 1 - (2-chloro-4-nitroim idazol-1-yl) - 4- (1-ethyl-1 H-tetrazol-5-yl) -2-methylbutan-2-ol (1.15 g, 69% yield) as a light yellow oil in the same manner as in Example 541.

[3231] ¹ H NMR (CDCb) δ ppm:

[3232] 1.29 (3H, s), 1.56 (3H, t, J = 7.3 Hz), 2.04 - 2.22 (2H, m), 2.91 - 3.11 (2H ,

m), 4.10 (2H, s), 4.24 (1H, br), 4.34 (2H, q, J = 7.3 Hz), 8.09 (1H, s).

[3233] Using corresponding starting materials, compounds of Examples 608 and 609 shown in the following table were obtained in the same manner as in Example 607.

Table 23

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739/854

Example R ³ HRMN (CDCU Ô Rend. (%) eos H 1.26 (3H, s), 2.02-2.08 (211. M), 2.96-3.17Í2H, m), 3.80Í1H, s), 4.04 (2H, 3), 7.42-7.46 (2H, m), 7.60- 7.62 (311, m), 8.03Ϊ1Η, s). 60 609 Cl 1.26 (3H, s), 2.08 · 2.12 (2Η, m), 2.96 * 3.15 (2H. M) _P 3.85 (1H, è), dM2B), 7.40-7.44Í2H, m), 7.56-7.61 (2H, m ), S.04I1H, a). 66

Example 610 [3234] Preparation of 2- [2- (1-ethyl-1 H-tetrazol-5-yl) ethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [3235 ] Using 1- (2-chloro-4-nitroimidazol-1-yl) -4- (1-ethyl-1 H-tetrazol-5-yl) -2methylbutan-2-ol prepared in Example 607 (1.15 g, 3.49 mmol) 2- [2- (1-ethyl 1 H-tetrazol-5-yl) ethyl] -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole ( 68 mg, 7% yield) as a light yellow powder in the same manner as in Example 544.

[3236] Melting point 135-137 ° C.

[3237] Using corresponding starting materials, compounds of Examples 611 and 612 were obtained in the same manner as in Example 610.

Example 611

2-methyl-6-nitro-2- [2- (1-phenyl-1 H-tetrazol-5-yl) ethyl] -2,3-dihydroimidazo [2,1-b] oxazole [3238] Melting point 158 -159 ° C.

Example 612

2- {2- [1- (4-chlorophenyl) -1 H-tetrazol-5-yl] ethyl} -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole [3239] Melting point 198-200 ° C.

Example 613

Preparation of 3- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl] -5- (4trifluoromethylbenzylidene) thiazolidine-2,4-dione [ 3240] Using 2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-yl) ethyl methanesulfonate prepared in Example 42 (280 mg, 0.96 mmol) and 5- ( 4trifluoromethylbenzylidene) thiazolidine-2,4-dione (320 mg, 1.17 mmol) 3- [2- (2methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) was obtained ) ethyl] -5- (4trifluoromethylbenzylidene) thiazolidine-2,4-dione (260 mg, 58% yield) as a light yellow powder in the same manner as in Example 537.

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740/854 [3241] Melting point 257-258.5 ° C.

Example 614

Preparation of 1 - [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] pyrrolidine-2,5dione [3242] Using 1- (2-methyloxyran-2-ylmethyl) pyrrolidine -2,5-dione (1.96 g, 11 mmol) 1 - [3- (2-chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methyl Ethyl] pyrrole was obtained ino-2.5dione (589 mg, 16% yield) as a white powder in the same manner as in Example 541.

[3243] ¹ H NMR (DMSO-de) δ ppm:

[3244] 0.96 (3H, s), 2.68 (4H, s), 3.48 (2H, s), 4.02 (2H, s), 5.19 (1H, s), 8, 34 (1H,

s).

[3245] Using corresponding starting materials, compounds of Examples 615 and 616 shown in the following table were obtained in the same manner as in Example 614.

Table 24

OH

Example R Ή NMR d (CDClj) Rend. 615 9 1.Ϊ1Ϊ3Η, ε), 3.48 (1H, $), 3.79Í1H, d, J = 14.6Hk), 3.90 (1H, d, J ~ 14.6Hz), 4.0Π1Η. d, J = 14.9 Hz), 4.16 (1H, d, J = 14.SHz), 7 75-7.93 (4H. m), 8.06 (1H), s). 71 616 ⁱⁱ '^ í 1.21Í3H, ₆ ), 4.09Í1H, d, J-14.4Hz), 4.1β (1Η, d. J-14.4Hz), 4.05Ϊ1Η, d, J = 14.3Hz), 4.15Í1H, d J = 14.3H _I ), 4.42 (1H, d, J = 14.0Hz), 4.49 (1H, d, J = 14.0Hz), 7.60-7.74Ϊ2Η, m), 7.81-0.12 (2H, m). 5Ξ

Example 617

Preparation of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) pyrrolidine-

2,5-dione

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741/854 [3246] Using 1 - [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] pyrrolidine-2,5-dione prepared in Example 614 (589 mg, 1, 86 mmol) 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) pyrrolidine-2,5dione (232 mg, 34% yield) was obtained as a white powder in the same way as in Example 544.

[3247] Melting point 202.5-203.4 ° C.

[3248] Using corresponding starting materials, compounds of Examples 618 and 619 were obtained in the same manner as in Example 617.

Example 618 2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) isoindole-1,3-dione [3249] Melting point 264.6-268, 3 ° C.

Example 619

2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1 -b] oxazol-2-ylmethyl) -1,1-dioxide-1,2-hydroxy [d] benzothiazole-3-one [3250] Melting point 243-245 ° C (decomposition).

Example 620

Preparation of 1 - (2-chloro-4-nitroimidazol-1-yl) -2- (pyridin-3-yl) -propan-2-ol [3251] Using 3- (2-methyloxyran-2-yl) pyridine ( 7.4 g, 54.75 mmol) 1- (2-chloro-4-nitroimidazol-1-yl) -2- (pyridin-3-yl) propan-2-ol (3.3 g, yield 24 %) as a white powder in the same way as in Example 541.

[3252] ¹ H NMR (CDCb) δ ppm:

[3253] 1.65 (3H, s), 4.19 (1H, d, J = 14.2 Hz), 4.27 (1H, d, J = 14.2 Hz), 5.82 (1H,

s), 7.24 - 7.30 (1H, m), 7.68 - 7.72 (1H, m), 8.50 - 8.53 (1H, m), 8.68 (1H, d, J = 2.3 Hz).

Example 621

Preparation of 2-methyl-6-nitro-2- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] oxazole [3254] Using 1 - (2-chloro-4-nitroimidazole-1 - yl) -2- (pyridin-3-yl) propan-2-ol prepared in Example 620 (3.3 g, 11.7 mmol) 2-methyl-6-nitro-2- (pyridin-3- il) -

2,3-dihydroimidazo [2,1-b] oxazole (1.8 g, 63% yield) as a light brown powder in the same manner as in Example 544.

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742/854 [3255] Melting point 212-214 ° C.

Example 622

Preparation of 2-methyl-6-nitro-2- (1-oxipyridin-3-yl) -2,3-dihydroimidazo [2,1-b] oxazole [3256] To a mixture of 2-methyl-6-nitro- 2- (pyridin-3-yl) -2,3-dihydroimidazo [2.1 b] oxazole prepared in Example 621 (800 mg, 3.3 mmol) and methylene chloride (25 ml), m- chloroperbenzoic acid (1 g, 4.06 mmol) with cooling in an ice bath, followed by stirring at room temperature overnight. The reaction mixture was filtered, and the filtrate was washed with a 20% aqueous sodium sulfite solution, a saturated sodium hydrogen carbonate solution and a saturated saline solution in that order, drying over magnesium sulfate and then filtering. The filtrate was concentrated under reduced pressure giving 2-methyl-6-nitro-2- (1-oxypyridin-

3-yl) -2,3-dihydroimidazo [2,1-b] oxazole (330 mg, 39%) as a white powder.

[3257] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3258] 1.92 (3H, s), 4.51 (2H, s), 7.42 - 7.53 (2H, m), 8.14 (1H, s), 8.20 - 8.24 (1H,

m), 8.42 (1H, s).

Example 623

Preparation of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) pieridin-4ona [3259] Using 1- (2-methyloxyran-2-ylmethyl) piperidin -4-one (2.2 g, 13 mmol) 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4-one was obtained (50 mg, 1% yield) as a light yellow powder in the same manner as in Example 597.

[3260] Melting point 124-126 ° C.

Example 624

Preparation of 4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] -1 - (4trifluoromethylbenzyl) piperazine-2-one [3261] Using 4- (2-methyloxyran-2-ylmethyl) -1 - (4-trifluoromethylbenzyl) piperazine-2one (1.6 g, 4.9 mmol) 4- [3- (2-chloro-4-nitroimidazole-1 - il) -2-hydroxy-2methylpropyl] -1- (4-trifluoromethylbenzyl) piperazine-2-one (1 g, 43% yield) as a light yellow powder in the same manner as in Example 541.

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743/854 [3262] ¹ H NMR (CDCb) δ ppm:

[3263] 1.18 (3H, s), 2.45 (1H, d, J = 13.9 Hz), 2.57 (1H, d, J = 13.9 Hz), 2.72-2, 98 (2H, m), 3.19 - 3.44 (3H, m), 3.55 (1H, d, J = 16.5 Hz), 4.00 (1H, d, J = 14.3 Hz ), 4.10 (1H, d, J = 14.3 Hz), 4.64 (2H, s), 7.37 (2H, d, J = 8.2 Hz), 7.61 (2H, d , J = 8.2 Hz), 8.02 (1H, s).

[3264] Using corresponding starting materials, the compound of Example 625 was obtained in the same manner as in Example 624.

Example 625

-Ter-butyl-4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-2-one [3265] ¹ H NMR (CDCb) δ ppm:

[3266] 1.16 (3H, s), 1.44 (9H, s), 2.41 (1H, d, J = 13.8 Hz), 2.51 (1H, d, J = 13.8

Hz), 2.65 - 2.88 (3H, m), 2.93 - 3.09 (1H, m), 3.12 - 3.28 (2H, m), 3.99 (1H, d, J = 14.3 Hz), 4.08 (1H, d, J = 14.3 Hz), 8.05 (1H, s).

Example 626

Preparation of 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1- (4trifluoromethylbenzyl) piperazine-2-one [3267] Using 4- [3 - (2-chloro-4-nitroim idazol-1-yl) -2-h idroxy-2-methylpropyl] -1 - (4trifluoromethylbenzyl) piperazine-2-one prepared in Example 624 (1 g, 2.1 mmol) 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1- (4trifluoromethylbenzyl) piperazine-2-one (206 mg, yield 22%) as a light yellow powder in the same manner as in Example 544.

[3268] Melting point 88-93 ° C.

[3269] Using corresponding starting materials, the compound of Example 627 was obtained in the same manner as in Example 626.

Example 627 1-Ter-butyl-4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-2-one [3270] Melting point 193- 194 ° C.

Example 628

Preparation of 1-ter-butyl-4- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2yl) ethyl] piperazine-2-one

Petition 870190039560, of 26/04/2019, p. 752/876

744/854 [3271] A mixture of 2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) methanesulfonate prepared in Example 42 (290 mg, 1 mmol) , 1-ter-butylpiperazine-2-one hydrochloride (200 mg, 1.28 mmol), triethylamine (242 mg, 2.39 mmol), potassium iodide (250 mg, 1.5 mmol) and DMF (3 ml ) was stirred at 70 ° C for 4 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water twice and a saturated saline solution, drying over magnesium sulfate and then filtering. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) giving 1-ter-butyl-4- [2- (2-methyl -6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2yl) ethyl] piperazine-2-one (27 mg, 8% yield) as a white powder.

[3272] Melting point 153-154 ° C.

[3273] Using corresponding starting materials, the compound of Example 629 was obtained in the same way as in Example 628.

Example 629

4- [2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) ethyl] -1-phenylpiperazine-2-one [3274] Melting point 199- 202 ° C (decomposition).

Example 630

Preparation of 1-ter-butyl-4- [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2yl) propyl] piperazine-2-one [3275] Using methanesulfonate 3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1b] oxazol-2-yl) propyl prepared in Example 39 (300 mg, 0.98 mmol) 1-terbutyl-4 was obtained - [3- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) propyl] piperazine-2-one (150 mg, 42% yield) as a powder white in the same way as in Example 628.

[3276] Melting point 147-149 ° C (decomposition).

Example 631

Preparation of 1 - (benzimidazol-1-yl) -3- (2-chloro-4-nitroimidazol-1-yl) -2-methylpropan-2-ol [3277] Using 1- (2-methyloxyran-2-ylmethyl) -1 H-benzimidazole (350 mg, 1.86 mmol)

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745/854 1 - (benzimidazol-1-yl) -3- (2-chloro-4-nitroimidazol-1-yl) -2-methylpropan-2-ol (135 mg, 22% yield) was obtained as a white powder in the same way as in Example 541.

[3278] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3279] 0.99 (3H, s), 4.06 (1H, d, J = 14.2 Hz), 4.23 - 4.45 (3H, m), 5.44 (1H, s),

7.14-7.32 (2H, m), 7.57 -7.77 (2H, m), 8.15 (1H, s), 8.36 (1H, s).

[3280] Using corresponding starting materials, the compound of Example 632 was obtained in the same manner as in Example 631.

Example 632

- (lmidazol-1-yl) -3- (2-chloro-4-nitroimidazole-1-yl) -2-methylpropan-2-ol [3281] ¹ H NMR (CDCb) δ ppm:

[3282] 1.19 (3H, s), 3.86 - 4.05 (3H, m), 4.13 (1H, d, J = 14.2 Hz), 6.87 (1H, s),

6.89 (1H, s), 7.47 (1H, s), 8.08 (1H, s).

Example 633

Preparation of 1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1 Hbenzimidazole [3283] Using 1 - (benzimidazol-1-yl) -3 - (2-chloro-4-nitroimidazol-1-yl) -2methylpropan-2-ol prepared in Example 631 (135 mg, 0.4 mmol) 1 - (2-methyl6-nitro-2,3-) was obtained dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1 H-benzimidazole (72 mg, 60% yield) as a white powder in the same manner as in Example 544.

[3284] Melting point 250.3-251.9 ° C (decomposition).

[3285] Using corresponding starting materials, the compound of Example 634 was obtained in the same manner as in Example 633.

Example 634

1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) imidazole [3286] Melting point 245.5-247.8 ° C.

Example 635

Preparation of (S) -1 - (2-chloro-4-nitroimidazol-1 -i 1) -3- (3,4-dihydro-2 H-quinol in-1 -yl) -2methylpropan-2- ol [3287] A mixture of (R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole

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746/854 prepared in Example 12 (100 mg, 0.46 mmol), 1,2,3,4-tetrahydroquinoline (122 mg, 0.92 mmol) and DMF (1 ml) was stirred at 80 ° C for 8 hours . The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washing with water twice and a saturated saline solution, drying over magnesium sulfate and then filtering. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane / ethyl acetate = 1/1) giving (S) -1 (2-chloro-4-nitroimidazole -1 -i 1) -3- (3,4-dihydro-2 H-quinol in-1 -yl) -2-methylpropan-2-ol (134 mg, 83% yield) as an orange oil.

[3288] ¹ H NMR (CDCb) δ ppm:

[3289] 1.24 (3H, s), 1.94 - 2.04 (2H, m), 2.39 (1H, m), 2.79 - 2.85 (2H, m), 3.27 3.42 (4H, m), 6.66 - 6.72 (2H, m), 6.97 - 7.08 (2H, m), 8.04 (1H, s).

[3290] Using corresponding starting materials, compounds of Examples 636 to 638 shown in the following table were obtained in the same manner as in Example 635.

Table 25

Example R Ή NMR â (CDCU Rend. (1) Ê36 CO 1.18 (8¾ fi), 2.51 (1¾ d, <1 = 13.SHU, 2.6ÊÍ1H, d _f J = 18.9Hi), 2.82 ^ 2.98 (4H, m), 3.76 (1H, d, J = 14.9Hz), 3.88 (1¾ d, J = 14.9Hz), 4.O3Í2H. s), 7.00 (1H, dd, 7.7 Hz), 7.06 * 7.20 (BH.ra), 8.01 (1H), s). 87 637 * 00 l.SDÍSH.s), 2.B5Í1H, d _f J = 13.8Hz), 2.71 (1¾ d, J = J3.8H2), 3.81 (1¾ d, J-14.3Hs), 8.91 (1¾ d, <1 = 14.8Hz), 4.0 & 4H, a), 7.10-7.23 (4¾ m), 3.00 (1¾ a). 93 638 0: 2 1.11 (3¾ b), 1.67-1.78 (4¾ m), 2.37 (1H, d, J = 14.0Hi), 2.51 (1H. D, 14.0Hz), 2.572.82 (4¾ m), 3.S & Í1H, e) , 3.95 (4¾ s), 3.99 (2¾ è), 8.06 (1¾ a). 100

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747/854

Example 639 [3291] Preparation of (S) -1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) -1,2,3,4-tetrahydroquinoline [3292 ] Using (S) -1 - (2-chloro-4-nitroimidazol-1-yl) -3- (3,4-dihydro-2H-quinolin-1-yl) 2-methylpropan-2-ol prepared in Example 635 (134 mg, 0.38 mmol) (S) -1 (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,2,3 , 4-tetrahydroquinoline (64 mg, 54%) as a white powder in the same manner as in Example 393.

[3293] Melting point 168-172 ° C.

[3294] Using corresponding starting materials, compounds of Examples 640 to 642 were obtained in the same manner as in Example 639.

Example 640 (S) -2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,2,3,4tetrahydroisoquinoline [3295] Melting point 153 -155.3 ° C.

Example 641 (S) -2- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -2,3-dihydro-1 H-isoindole [3296] ¹ H NMR (CDCb) δ ppm:

[3297] 1.68 (3H, s), 3.01 (1H, d, J = 14.5 Hz), 3.24 (1H, d, J = 14.5 Hz), 3.92 (1H, d, J = 9.6 Hz), 4.08 (4H, s), 4.50 (1H, d, J = 9.6 Hz), 7.13-7.21 (4H, m), 7, 50 (1H, s). Example 642 (S) -8- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -1,4-dioxa-8azaospiro [4,5] decane [ 3298] Melting point 166.5-168.2 ° C.

Example 643

Preparation of (2S) -methyl-6-nitro-2 - [(2S) - (4-trifluoromethoxyphenoxymethyl) pyrrolidin-1 ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole [3299] A mixture of ( R) -2-chloro-1- (2-methyloxyran-2-ylmethyl) -4-nitroimidazole prepared in Example 12 (645 mg, 2.97 mmol), (S) -2- (4trifluoromethoxyphenoxymethyl) pyrrolidine (930 mg , 3.56 mmol) and DMF (15 ml) was stirred at 80 ° C for 8 hours. To the reaction mixture, sodium hydride (154 mg,

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748/854

3.86 mmol), followed by stirring for 1 hour with cooling in an ice bath. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washing with water twice and a saturated saline solution, drying over magnesium sulfate and then filtering. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride) and recrystallized from methylene chloride-isopropyl ether giving (2S) -methyl6-nitro-2- [ (2S) - (4-trifluoromethoxyphenoxymethyl) pyrrolidin-1-ylmethyl] -2,3-dihydroimidazo [2,1b] oxazole (505 mg, 41% yield) as a white powder.

[3300] ¹ H NMR (CDCb) δ ppm:

[3301] 1.42 - 1.52 (1H, m), 1.59 (3H, s), 1.61 - 1.79 (2H, m), 1.87 - 1.99 (1H, m) ,

2.50 - 2.61 (1H, m), 3.03 - 3.17 (2H, m), 3.06 (1H, d, J = 14.7 Hz), 3.20 (1H, d, J = 14.7 Hz), 3.72 - 3.79 (2H, m), 3.92 (1H, dd, J = 9.2 Hz, 3.7 Hz), 4.58 (1H, d, J = 9.5 Hz), 6.80-6.88 (2H, m), 7.15-7.19 (1H, m), 7.42 (1H, s).

Example 644

Preparation of tert-butyl 4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] homopiperazine-1-carboxylate [3302] A mixture of 2-chloro-4-nitro- 1 H-imidazole (8.39 g, 56.88 mmol), tert-butyl 4- (2methyloxyran-2-ylmethyl) homopiperazine-1-carboxylate (15.38 g, 56.88 mmol) and sodium acetate ( 5.13 g, 62.57 mmol) in 1-propanol (100 ml) was stirred at reflux for 10 hours. The reaction mixture was allowed to return to room temperature and then concentrated under reduced pressure. The residue was dissolved in methylene chloride. The solution was washed with water, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 5/1) giving 4- [3- (2-chloro-4-nitroimidazole -1-yl) -2-hydroxy-2-methylpropyl] ter-butyl homopiperazine-1-carboxylate (6.25 g, 27% yield) as a reddish yellow oil.

[3303] ¹ H NMR (CDCb) δ ppm:

[3304] 1.14 (3H, s), 1.48 (9H, s), 1.69 -1.90 (2H, m), 2.40 - 2.55 (1H, m), 2.66 (1H,

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749/854 d, J = 14.1 Hz), 2.75 - 2.98 (5H, m), 3.30 - 3.59 (4H, m), 3.96 (2H, s), 8, 06 (1H, s). Example 645

Preparation of tert-butyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) homopiperazine-1-carboxylate [3305] Using 4- [3- (2- chloro-4-nitroimidazole-1-yl) -2-hydroxy-2-methylpropyl] homopiperazine-1-tert-butylcarboxylate prepared in Example 644 (6.25 g, 14.96 mmol) 4- (2- tert-butyl methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) homopiperazine-1-carboxylate (3.07 g, 54% yield) as a white powder in the same way as in Example 544.

[3306] ¹ H NMR (CDCb) δ ppm:

[3307] 1.47 (9H, s), 1.59 (3H, s), 1.68 -1.79 (2H, m), 2.63 - 2.90 (5H, m), 3.06 (1H, d, J = 15.1 Hz), 3.25 - 3.50 (4H, m), 3.91 (1H, d, J = 9.7 Hz), 4.33 (1H, d, J = 9.7 Hz), 7.54 (1H, s).

Example 646

Preparation of benzyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) homopiperazine-1-carboxylate [3308] A mixture of 4- (2-methyl -6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) homopiperazine-1-tert-butylcarboxylate prepared in Example 645 (250 mg, 0.655 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride (10 ml). Triethylamine (0.27 ml, 1.96 mmol) and benzyl chloroformate (0.19 ml, 1.31 mmol) were added to the solution, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 1/1) giving a light yellow oil. The resulting oil was dissolved in ethyl acetate. A saturated hydrochloric acid / ethyl acetate solution was added to the solution, and the precipitates were removed by filtration giving 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole hydrochloride -2

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Benzyl 750/854 ylmethyl) homopiperazine-1-carboxylate (246 mg, 83% yield) as a white powder.

[3309] Melting point 115-117 ° C.

Example 647

Preparation of 2- [4- (biphenyl-4-ylmethyl) homopiperazin-1-i Imethyl] -2-methyll-6-n-itro-2,3dihydroimidazo [2,1-b] oxazole [3310] One mixture of tert-butyl 4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl) homopiperazine-1-carboxylate prepared in Example 645 (346 mg, 0.91 mmol ) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). Triethylamine (0.27 ml, 1.96 mmol) was added to the solution. The solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-phenylbenzaldehyde (496 mg, 2.72 mmol), sodium cyanotrihydroborate (171 mg, 2.72 mmol) and acetic acid (0.17 ml, 2.72 mmol) were added in this order, followed by stirring. at room temperature overnight. The reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, then extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 5/1) giving 2- [4- (biphenyl-4-ylmethyl) homopiperazin -1-ylmethyl] -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole (251 mg, 62% yield) as a white powder.

[3311] Melting point 138-142.2 ° C.

Example 648

Preparation of T-ter-butoxycarbonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] [3312] 2,4-Dinitro-1 H-imidazole (1, 0 g, 6.3 mmol), tert-butyl 1-oxa-6azaospiro [2.5] octane-6-carboxylate (2.0 g, 9.5 mmol) and sodium acetate (612 mg, 7.5 mmol ) in ethanol (7 ml) were stirred at reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. A solution was added to the residue

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751/854 saturated sodium hydrogen carbonate and methylene chloride, followed by vigorous stirring, and then the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was crystallized from methylene chloride-diisopropyl ether giving T-ter-butoxycarbonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol2,4 '-piperidine] (586 mg, 29% yield) as a white powder.

[3313] Melting point 230-232 ° C.

Example 649

Preparation of tert-butyl 4- (2-chloro-4-nitroimidazole-1-methyl) -4-hydroxypiperidine-1-carboxylate [3314] 2-chloro-4-nitro-1 H -imidazole (3.1 g , 21.0 mmol), 1-oxa-6azaospiro [2.5] octane-6-carboxylate (4.4 g, 21.0 mmol) and sodium hydrogen carbonate (1.94 g, 23.1 mmol ) in ethanol (20 ml) were stirred at reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added water. The resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 4 (2-chloro-4-nitroimidazole-1-methyl) Tert-butyl -4-hydroxypiperidine-1-carboxylate (5.4 g, 72% yield) as a yellow oil.

[3315] ¹ H NMR (CDCb) δ ppm:

[3316] 1.45 - 1.71 (5H, m), 1.46 (9H, s), 3.03-3.14 (2H, m), 3.90 -4.03 (2H, m) ,

4.02 (2H, s), 7.91 (1H, s).

Example 650

Preparation of tert-butyl 4- {2- [4- (2-chloro-4-nitroimidazol-1-i-imethyl) -4-h-idroxypiperid-1-yl] -2oxoethyl} piperazine-1-carboxylate [ 3317] 2-chloro-4-nitro-1 H -imidazole (1.29 g, 8.76 mmol), 4- {2- (1-oxa-6azaospiro [2.5] octan-6-yl) - Tert-butyl 2-oxoethyl} piperazine-1-carboxylate (2.97 g, 8.76 mmol) and sodium hydrogen carbonate (809 mg, 9.64 mmol) in ethanol (10 ml) was stirred at reflux for 5 hours . The reaction mixture was concentrated under pressure

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752/854 reduced, and a saturated sodium hydrogen carbonate solution was added. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) giving 4- {2- [4- (2-chloro-4 -nitroim idazol-1-ylmethyl) 4-hydroxypiperidin-1-yl] -2-oxoethyl} ter-butyl piperazine-1-carboxylate (2.58 g, 61% yield) as a yellow oil.

[3318] ¹ H NMR (CDCb) δ ppm:

[3319] 1.45 (9H, s), 1.53-1.71 (4H, m), 2.44 (4H, br), 2.96 - 3.04 (1H, m), 3.10 3.27 (2H, m), 3.35 - 3.48 (4H, m), 3.90 - 3.96 (2H, m), 4.05 (2H, s), 4.32 - 4, 37 (2H, m), 8.04 (1H, s).

[3320] Using 6- (4-trifluoromethylphenyl) -1-oxa-6-azospiro [2.5] octane the compound of Example 651 was obtained in the same manner as in Example 650.

Example 651 4- (2-chloro-4-nitroimidazol-1-ylmethyl) -1- (4-fluoromethylphenyl) piperidin-4-ol [3321] Light pink powder, 54% yield [3322] ¹ H NMR (CDCb) δ ppm:

[3323] 1.60-1.66 (2H, m), 1.82 -1.93 (3H, m), 3.10-3.22 (2H, m), 3.62 -3.67 ( 2H,

m), 4.07 (2H, s), 6.95 (2H, d, J = 8.7 Hz), 7.50 (2H, d, J = 8.7 Hz), 7.99 (1H, s). Example 652

Preparation of 1'-ter-butoxycarbonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] (alternative synthesis method of the compound of Example 648) [3324] 4- (Terbutyl 2-chloro-4-nitroimidazol-1-ylmethyl) -4-hydroxypiperidine-1-carboxylate prepared in Example 649 (26.7 g, 74.0 mmol) was dissolved in 1,4-dioxane (200 ml) . Sodium hydride (3.6 g, 88.8 mmol) was added to the solution with cooling in an ice bath, followed by stirring at reflux for 8 hours. The reaction mixture was concentrated under reduced pressure. Ice water and methylene chloride were added to the residue, followed by vigorous stirring. The precipitates were removed by filtration, washed with water and methanol, dried under reduced pressure to give a solid (16.4 g). Then, the filtrate was extracted with methylene chloride. The phase

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753/854 organic was dried over magnesium sulfate and then filtered. The organic phase was concentrated under reduced pressure. The residue was crystallized from methanol giving a solid (2.7 g). The solids were combined giving T-ter-butoxycarbonyl-2,3-dihydro-6 nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] (19.1 g, 79% yield) as a powder White.

[3325] Melting point 230-232 ° C.

Example 653

Preparation of 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] -Til) -2-oxoethyl] piperazine-1-carboxylate -butyl [3326] 4- {2- [4- (2-chloro-4-nitroim idazol-1-i Imethyl) -4-h idroxypiperid in-1 -yl] -2oxoethyl} piperazine ter-butyl carboxylate prepared in Example 650 (2.58 g, 5.3 mmol) was dissolved in dioxane (30 ml). Sodium hydride (254 mg, 6.36 mmol) was added to the solution with cooling in an ice bath, followed by stirring at reflux overnight. The reaction mixture was concentrated under reduced pressure. Ice water and ethyl acetate were added to the residue, followed by vigorous stirring. The precipitates were removed by filtration, washed with water and ethyl acetate, and then dried under reduced pressure giving 4- [2- (2,3-dihydro-6nitrospiro [imidazo [2,1-b] oxazol-2,4 ' -piperidine] -T-yl) -2-oxoethyl] ter-butyl piperazine-1carboxylate (996 mg, 42% yield) as a white powder.

[3327] Melting point 211.0-213.0 ° C.

[3328] Using corresponding starting materials, the compound of Example 654 was obtained in the same way as in Example 653.

Example 654 2,3-dihydro-6-nitro-T- (4-trifluoromethylphenyl) spiro [imidazo [2,1-b] oxazol-2,4'-pipendine] [3329] White powder, 79% yield [3330 ] Mass Spectrum: 368 (M ⁺ ) [3331] Melting point 249.2-250.1 ° C.

Example 655

Preparation of 2,3-dihydro-6-nitrospiro trifluoroacetate [imidazo [2,1-b] oxazol-2,4'piperidine]

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754/854 [3332] T-Ter-butoxycarbonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 652 (42 g, 0.13 mol ) was suspended in methylene chloride (100 ml). Trifluoroacetic acid (60 ml) was added slowly to the suspension with cooling in an ice bath, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol. The solids were removed by filtration, washed with methanol and ethyl acetate, and then dried under reduced pressure giving 2,3-dihydro-6-nitrospiro trifluoroacetate [imidazo [2,1-b] oxazol-2,4'-piperidine ] (43.6 g, 99% yield) as a light brown powder.

[3333] Mass Spectrum: 224 (M ⁺ ) [3334] Melting point 196-198 ° C (decomposition) [3335] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3336] 2.06 - 2.32 (4H, m), 3.12 - 3.35 (4H, m), 4.24 (2H, s), 8.21 (1H, s), 8.88 (2H, bs).

Example 656

Preparation of T-acetyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] [3337] 2,3-dihydro-6-nitrospiro trifluoroacetate [imidazo [ 2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (85.5 mg, 0.25 mmol) was suspended in methylene chloride (5 ml). Triethylamine (74 μΙ) and acetyl chloride (20 μΙ) were added to the suspension, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Methanol and water were added to the residue, followed by vigorous stirring. The precipitates were removed by filtration, washed with water and isopropyl ether, and then dried under reduced pressure giving T-acetyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4 ' -piperidine] (37.8 mg, 56% yield) as a white powder.

[3338] Mass Spectrum: 266 (M ⁺ ) [3339] Melting point 232.0-234.0 ° C.

Example 657

Preparation of T- (4-trifluoromethylphenylacetyl) -2,3-dihydro-6-nitrospiro [imidazo [2,1b] oxazol-2,4'-piperidine]

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755/854 [3340] 2,3-dihydro-6-nitrospiro trifluoroacetate [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (300 mg, 0.89 mmol) was suspended in methylene chloride (5 ml). Triethylamine (0.4 ml, 2.66 mmol) and (oc, oc, oc-trifluoro-p-tolyl) acetyl chloride (2.7 ml, 1.33 mmol) were added to the suspension, followed by stirring. at room temperature for 1 hour. The reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving 1 '- ( 4-trifluoromethylphenylacetyl) -2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] (143 mg, 39% yield) as a white powder.

[3341] Mass Spectrum: 410 (M ⁺ ) [3342] Melting point 185.0-187.0 ° C.

Example 658

Preparation of 1 '- (3,4-dichlorophenoxyacetyl) -2,3-dihydro-6-nitrospiro [imidazo [2,1b] oxazol-2,4'-piperidine] [3343] 2,3-dihydro-6 trifluoroacetate -nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (300 mg, 0.89 mmol), (3.4dichlorophenyl) acetic acid (294 mg, 1.24 mmol) and WSCD (255 mg, 1.24 mmol) in DMF (5 ml) were stirred at room temperature for 1.5 hours. Water and diethyl ether were added to the reaction mixture, followed by vigorous stirring. The precipitates were removed by filtration, washed with water and diethyl ether, and then dried under reduced pressure to give 1 '- (3,4-dichlorophenoxyacetyl) -2,3-dihydro-6nitrospiro [imidazo [2,1-b] oxazole -2,4'-piperidine] (96 mg, 25% yield) as a white powder.

[3344] Melting point 218.0-220.0 ° C.

Example 659

Preparation of 2,3-dihydro-1'-methyl-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] [3345] 2,3-dihydro-6-nitrospiro [imidazo [2 , 1-b] oxazole-2,4'-piperidine] (250 mg, 1.12

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756/854 mmol) obtained by neutralizing 2,3-dihydro-6-nitrospiro trifluoroacetate [imidazo [2,1-b] oxazol-2,4'-piperidine] prepared in Example 655 was suspended in methanol (5 ml) . To the suspension, a 37% formaldehyde solution (0.25 ml, 3.35 mmol), sodium cyanotrihydroborate (210 mg, 3.35 mmol) and acetic acid (0.19 ml, 3.35 mmol) were added to the suspension. ), followed by stirring at room temperature for 3 hours. The reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, and the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was crystallized from methylene chloride-diisopropyl ether giving 2,3-dihydro-1'-methyl-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] (160 mg, 60% yield ) as a white powder.

[3346] Mass Spectrum: 238 (M ⁺ ) [3347] Melting point 237.0-239.0 ° C (decomposition).

Example 660

Preparation of 1'-benzenesulfonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] [3348] 2,3-dihydro-6-nitrospiro trifluoroacetate [imidazo [ 2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (197 mg, 0.88 mmol) was suspended in methylene chloride (5 ml). Triethylamine (0.36 ml, 2.64 mmol) and benzenesulfonyl chloride (0.28 ml, 2.10 mmol) were added to the suspension, followed by stirring at room temperature for 30 minutes. Diisopropyl ether and water were added to the reaction mixture, followed by vigorous stirring. The precipitates were removed by filtration, washed with water and diisopropyl ether, and then dried under reduced pressure to give 1'-benzenesulfonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4 'piperidine] (210 mg, 66% yield) as a white powder.

[3349] Mass Spectrum: 364 (M ⁺ ) [3350] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3351] 1.99-2.18 (4H, m), 2.49 -2.63 (2H, m), 3.40-3.54 (2H, m), 4.10 (2H, s) ,

7.65-7.81 (5H, m), 8.21 (1H, s).

[3352] Using the corresponding starting materials, the compound of

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Example 661 in the same way as in Example 660.

Example 661 T-methanesulfonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] [3353] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3354] 1.98 -2.22 (4H, m), 2.94 (3H, s), 3.04-3.13 (2H, m), 3.43-3.51 (2H, m) ,

4.16 (2H, s), 8.17 (1H, s).

Example 662

Preparation of 1'-benzyloxycarbonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] [3355] 2,3-dihydro-6-nitrospiro trifluoroacetate [imidazo [ 2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (250 mg, 0.74 mmol) was suspended in methylene chloride (5 ml). Triethylamine (0.40 ml, 2.96 mmol) and benzyl chloroformate (0.32 ml, 2.22 mmol) were added to the suspension, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving 1'- benzyloxycarbonyl-2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol2,4'-piperidine] (224 mg, 84% yield) as a white powder.

[3356] Melting point 175.0-177.0 ° C.

Example 663

Preparation of 1 '- (4-trifluoromethylbenzyloxycarbonyl) -2,3-dihydro-6nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] [3357] 2,3-dihydro-6-nitrospiro trifluoroacetate [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (33 g, 97.6 mmol) was suspended in DMF (200 ml). Triethylamine (20 ml, 0.15 mol) was added to the suspension, followed by stirring. A mixture of 4-trifluoromethylbenzyl alcohol (25.8 g, 0.15 mol), 1, T-carbonyldiimidazole (23.7 g, 0.15 mol) and DMF (100 ml) stirred at temperature was added to the solution room for 3 hours, followed by stirring at 70 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the precipitates were removed by filtration. The precipitates were purified by means of

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758/854 column chromatography on silica gel (methylene chloride / ethyl acetate = 10/1) and recrystallized from ethyl acetate-isopropyl ether giving T- (4trifluoromethylbenzyloxycarbonyl) -2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] (37.2 g, 90% yield) as a white powder.

[3358] Melting point 189-190 ° C.

[3359] Using corresponding starting materials, compounds of Examples 664 and 665 were obtained in the same manner as in Example 663.

Example 664

T - [(4-trifluoromethoxy) benzyloxycarbonyl] -2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol2,4'-piperidine] [3360] ¹ H NMR (CDCb) δ ppm:

[3361] 1.80 -1.93 (2H, m), 2.13 - 2.19 (2H, m), 3.32 - 3.42 (2H, m), 4.00 - 4.20 ( 2H,

m), 4.03 (2H, s), 5.14 (2H, s), 7.20 - 7.23 (2H, m), 7.38 - 7.46 (2H, m), 7.54 (1H, s). Example 665

T- (4-Formylaminobenzyloxycarbonyl) -2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol2,4'-piperidine] [3362] ¹ H NMR (DMSO-de) δ ppm:

[3363] 1.85-2.10 (4H, m), 3.15 - 3.40 (2H, m), 3.65 - 3.85 (2H, m), 4.16 (2H, s) ,

5.03 (2H, s), 7.33 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 8.15 (1H, s), 8.27 (1H, s).

Example 667

Preparation of 2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] -1 '-carboxylic acid phenylamide [3364] 2,3-dihydro-6- trifluoroacetate nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (100 mg, 0.30 mmol) was suspended in DMF (5 ml). Triethylamine (43 μΙ, 0.31 mmol) and phenylisocyanate (34 μΙ, 0.31 mmol) were added to the suspension, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, followed by stirring, and the precipitates were removed by filtration. The precipitates were purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and

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[3365] MS; 343 (M ⁺ ) [3366] Melting point 229-232 ° C (decomposition).

[3367] Using pyridine 4-isocyanate or benzyl isocyanate gave compounds of Examples 668 and 669 in the same manner as in Example 667.

Example 668

2,3-Dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] 1'-carboxylic acid 4-pyridinamide [3368] Melting point 217-219 ° C.

Example 669 2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] -Tcarboxylic acid benzylamide [3369] Melting point 244-247 ° C (decomposition).

Example 670

Preparation of tert-butyl 4- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] -Tilcarbonyl) piperazine-1-carboxylate [3370] Triphosgene (227 mg, 0.77 mmol) was dissolved in toluene (10 ml). Terbutyl piperazine-1-carboxylate (425 mg, 2.28 mmol) and diisopropylethylamine (0.4 ml, 2.28 mmol) were added to the solution, followed by stirring for 1 hour with cooling in an ice bath. 2,3-Dihydro6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] trifluoroacetate prepared in Example 655 (700 mg, 2.07 mmol) was added to the solution. The solution was stirred at room temperature for 1 hour and then stirred at reflux for 1 hour. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / acetone = 10/1) and then crystallized from methylene chloride-diisopropyl ether giving 4- (2,3-dihydro-6

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760/854 nitrospiro [im idazo [2,1-b] oxazol-2,4'-piperidine] -1 '-ylcarbonyl) terp-butyl-1-carboxylate (342 mg, 38% yield) as a powder White.

[3371] Melting point 260.0-265.0 ° C (decomposition).

[3372] ¹ H NMR (CDCb) δ ppm:

[3373] 1.47 (9H, s), 1.90 - 2.02 (2H, m), 2.10 - 2.16 (2H, m), 3.23 - 3.47 (10H, m) ,

3.60 - 3.66 (2H, m), 3.96 (2H, s), 7.54 (1H, s).

[3374] Using benzyl 4-trifluoromethylpiperazine-1-carboxylate or 1- (4trifluoromethylbenzyl) piperazine, compounds of Examples 671 and 672 were obtained in the same manner as in Example 670.

Example 671 4- 4-Trifluoromethylbenzyl 4- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -1'-ylcarbonyl) piperazine-1-carboxylate [3375] melting 221 -223 ° C.

Example 672 1- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -1'-ylcarbonyl) -4- (4trifluoromethylbenzyl) piperazine [3376] melting 226-230 ° C (decomposition).

Example 673

Preparation of 2,3-dihydro-6nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -1'-carboxylic acid 4- (dimethylamino) phenylamide [3377] 2,3-dihydro trifluoroacetate -6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (200 mg, 0.59 mmol) was suspended in DMF (5 ml). Triethylamine (0.1 ml, 0.72 mmol) was added to the suspension, followed by stirring. A mixture of N, N-dimethyl-p-phenylenediamine (132 mg, 0.98 mmol), 1,1'-carbonyldiimidazole (82.7 mg, 1.02 mmol) and DMF (5 ml) was added to the solution stirred at room temperature for 3 hours, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, followed by stirring, and the precipitates were removed by filtration. The precipitates were purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from ethyl acetate giving 2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazole

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2,4'-piperidine] -1 '-carboxylic acid 4- (dimethylamino) phenylamide (181 mg, 79% yield) as a white powder.

[3378] MS 386 (M ⁺ ) [3379] Melting point 244-247 ° C (decomposition).

[3380] Using 4-trifluoromethylbenzylamine or 4-trifluoromethoxybenzylamine, compounds of Examples 674 and 675 were obtained in the same manner as in Example 673.

Example 674

2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] -1'-carboxylic acid 4-trifluoromethylbenzylamide [3381] Melting point 215-217 ° C.

Example 675

2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol2,4'-piperidine] -1'-carboxylic acid 4-trifluoromethoxybenzylamide [3382] Melting point 223-225 ° C.

Example 676

Preparation of 2,3-dihydro-6-nitrospiro [imidazo [2,1b] oxazol-2,4'-piperidine] -1'-carbothioic acid 4-chlorophenylamide [3383] 2,3-dihydro-6- trifluoroacetate nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (200 mg, 0.59 mmol) was suspended in DMF (5 ml). Triethylamine (0.24 ml, 1.77 mmol) and 4-chlorophenyl isothiocyanate (200 mg, 1.18 mmol) were added to the suspension, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, followed by stirring, and the precipitates were removed by filtration, purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from methylene chloride- diisopropyl ether giving 2,3-dihydro-6nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] -1'-carbothioic acid 4-chlorophenylamide (222 mg, 87% yield) as a White powder.

[3384] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3385] 2.02 - 2.19 (4H, m), 3.59 - 3.69 (2H, m), 4.19 (2H, s), 4.40 - 4.54 (2H, m) ,

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7.30-7.37 (4H, m), 8.18 (1H, s), 9.48 (1H, s).

Example 677

Preparation of 4 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) 1 '-ylcarbonyl] aminobenzoic acid [3386] 4 - [(2, 3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - Tylcarbonyl] tert-butyl aminobenzoate (150 mg, 0.68 mmol) was dissolved in methylene chloride ( 1 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from methanol-ethyl acetate giving 4 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - Tylcarbonyl] aminobenzoic acid (59 mg, 45% yield) as a white powder.

[3387] Melting point> 300 ° C.

[3388] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3389] 1.92-2.12 (4H, m), 3.32 - 3.39 (2H, m), 3.86 - 3.95 (2H, m), 4.17 (2H, s) ,

7.45 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J = 8.8 Hz), 8.17 (1H, s), 8.97 (1H, s), 12.54 (1H, s).

Example 678

Preparation of 2 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - Tyl] benzothiazole [3390] 2,3-dihydro-6 trifluoroacetate -nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (84 mg, 0.25 mmol) was suspended in DMF (3 ml). Triethylamine (76 μΙ, 0.55 mmol) and 2-chlorobenzothiazole (40 μΙ, 0.30 mmol) were added to the suspension, followed by stirring at 80 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the precipitate was removed by filtration, crystallized from methylene chloride-methanol giving 2 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4 ' -piperidine]) - 1'-yl] benzothiazole (55 mg, 62% yield) as a white powder.

[3391] MS; 357 (M ⁺ ) [3392] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3393] 2.05 - 2.23 (4H, m), 3.52 - 3.63 (2H, m), 3.89 - 3.97 (2H, m), 4.18 (2H, s) ,

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7.05 - 7.12 (1H, m), 7.26 - 7.32 (1 Η, m), 7.46 - 7.49 (1 Η, m), 7.76 - 7.80 (1 Η, m), 8.18 (1H, s).

[3394] Using 5-chloro-1-phenyl-1 H-tetrazole, the compound of Example 679 was obtained in the same manner as in Example 678.

Example 679 5 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - T-yl] -1-phenyl-1 Htetrazole [3395] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3396] 2.05 - 2.09, (4H, m), 3.24 - 3.40 (4H, m), 4.14 (2H, s), 7.59 - 7.72 (5H, m ),

8.15 (1H, s).

Example 680

Preparation of tert-butyl 4 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - Tylacetyl] piperazine-1-carboxylate [3397] Trifluoroacetate 2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] prepared in Example 655 (700 mg, 2.07 mmol) was suspended in DMF (20 ml). To the suspension were added ter-butyl 4- (chloroacetyl) piperazine-1-carboxylate (599 mg, 2.28 mmol), N, N-diisopropylethylamine (0.8 ml, 4.57 mmol) and sodium iodide ( 310 mg, 2.07 mmol), followed by stirring at 100 ° C for 3 hours. The reaction mixture was allowed to return to room temperature. Ethyl acetate and water were added to the solution, followed by vigorous stirring. The precipitates were removed by filtration, washed with water and ethyl acetate, and then dried under reduced pressure to give 4 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4 ' -piperidin]) - Tylacetyl] terp-butyl piperazine-1-carboxylate (688 mg, 74% yield) as a white powder.

[3398] Melting point> 300 ° C.

[3399] ¹ H NMR (DMSO-d ₆ ) δ ppm:

[3400] 1.41 (9H, s), 1.95 - 2.01 (4H, m), 2.43 - 2.64 (4H, m), 3.21 (2H, s), 3.26 3.42 (6H, m), 3.50 - 3.52 (2H, m), 4.12 (2H, s), 8.14 (1H, s).

[3401] Using 2-chloro-N- (4-trifluoromethylphenyl) acetamide or 3- (3-chloropropyl) -3Hbenzoxazol-2-one the compounds of Examples 681 and 682 were obtained in the same way

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764/854 than in Example 680.

Example 681 (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidin]) - 1'-ylacetic [3402] melting point 273 (4-trifluoromethylphenyl) amide -275 ° C (decomposition).

Example 682 3- [3- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - T-yl] propyl-3Hbenzoxazol-2-one [3403 ] Melting point 190-192 ° C.

Example 683

Preparation of tert-butyl 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - Tylethyl] piperazine-1-carboxylate [3404 ] 2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidine] trifluoroacetate prepared in Example 655 (200 mg, 0.59 mmol) was suspended in DMF (5 ml) . To the suspension, tert-butyl 4- (2-chloroethyl) piperazine-1-carboxylate (150 mg, 0.60 mmol), triethylamine (0.25 ml, 1.79 mmol) and sodium iodide (108 mg, 0.72 mmol), followed by stirring at 50 ° C for 5 hours. The reaction mixture was allowed to return to room temperature. Ethyl acetate and water were added to the solution, followed by vigorous stirring. The precipitates were removed by filtration, washed with water and ethyl acetate, and then dried under reduced pressure giving 4- [2- (2,3-hydroxy-6-nitrospiro [imidazo [2,1-b] oxazol-2,4 ' -piperidin]) - tert-butyl 1'-ylethyl] piperazine-1carboxylate (80 mg, 31% yield) as a white powder.

[3405] Melting point 214-215 ° C.

Example 684

Preparation of 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -T-yl) 2-oxoethyl] piperazine-1-carboxylate 4-trifluromethylbenzyl [3406] 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -T-yl) -2oxoethyl] piperazine-1 tert-butyl carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 6 hours.

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The reaction mixture was concentrated under reduced pressure. Methylene chloride (1 ml) and triethylamine (1 ml) were added to the residue. The reaction mixture was stirred at room temperature for 5 minutes and concentrated under reduced pressure, and the residue was dissolved in DMF (15 ml). A mixture of 4-trifluoromethylbenzyl alcohol (293 mg, 1.67 mmol), 1, Τ-carbonyldiimidazole (270 mg, 1.67 mmol) and DMF (5 ml) stirred at room temperature for 3 hours was added to the solution , followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over magnesium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving 4- [2- (2,3-dihydro-6nitrosospiro [ 4-trifluromethylbenzyl imidazo [2,1-b] oxazol-2,4'-piperidin] -T-yl) -2-oxoethyl] piperazine-1-carboxylate (324 mg, 88% yield) as a light pink powder . [3407] MS 553 (M + H) ⁺ [3408] Melting point 139.0-141.0 ° C.

[3409] Using corresponding starting materials, the compound of Example 685 was obtained in the same way as in Example 684.

Example 685 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -T-yl) -2oxoethyl] piperazine-1-carboxylate 4 -trifluoromethoxybenzyl [3410] Melting point 137-139 ° C.

[3411] Using 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'piperidin]) - T-ylethyl] piperazine-1-carboxylate ter- butyl prepared in Example 683, compounds of Examples 686 to 689 were obtained in the same manner as in Example 684.

Example 686 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - T-ylethyl] piperazino-1-4-chlorobenzyl [3412 ] Melting point 178-179 ° C.

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Example 687 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - 1'-ylethyl] piperazine-1-carboxylate 4-trifluoromethylbenzyl [ 3413] Melting point 174-175 ° C.

Example 688

4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - 1'-ethylethyl] piperazine-1 4-trifluoromethoxybenzyl carboxylate [3414 ] Melting point 176-177 ° C.

Example 689

4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - 1'-ethylethyl] piperazine-1 biphenyl-4-ylmethyl carboxylate [3415] ¹ H NMR (CDCb) δ ppm:

[3416] 1.90 - 2.05 (2H, m), 2.15 - 2.20 (2H, m), 2.40 - 2.80 (12H, m), 3.45 - 3.60 ( 4H, m), 3.99 (2H, s), 5.17 (2H, s), 7.31 - 7.62 (10H, m).

[3417] Using 4 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] 1'-ylacetyl) piperazine-1-carboxylate prepared in Example 680, the compound of Example 690 was obtained in the same manner as in Example 684.

Example 690 4- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - 1'-ylacetyl] piperazino-1carboxylate 4-trifluoromethylbenzyl [3418] Point melting temperature 137-139 ° C.

Example 691

Preparation of 1 - (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - 1 '-yl) -2 [4- (4-trifluoromethylbenzyl) piperazin -1-yl] ethanone [3419] 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] -1'-yl) -2oxoethyl ] tert-butyl piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (10 ml) was added to the solution, followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride (1 ml) and triethylamine (1 ml) were added to the solution, followed by stirring at room temperature.

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767/854 room for 5 minutes. The solution was concentrated under reduced pressure and the residue was dissolved in methanol (10 ml). To the solution, 4trifluoromethylbenzaldehyde (0.23 ml, 1.67 mmol), sodium cyanotrihydroborate (105 mg,

1.67 mmol) and acetic acid (0.1 ml) with cooling in an ice bath, followed by stirring at room temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate and methylene chloride was added to the solution, followed by stirring. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride / methanol = 50/1) and crystallized from methylene chloride-diisopropyl ether giving 1- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin]) - T-yl) -2- [4- (4thfluoromethylbenzyl) piperazin-1-yl] ethanone (226 mg, 67% yield) as a powder White.

[3420] MS 508 (M) ⁺ [3421] Melting point 145-147 ° C.

[3422] Using corresponding starting materials, the compound of Example 692 was obtained in the same way as in Example 691.

Example 692 1- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-pipehdin] -T-yl) -2 - [(4phenylbenzyl) piperazin-1-yl] ethanone [3423] Melting point 187-188 ° C.

[3424] Using 4- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -1 'ilacetyl) piperazine-1-carboxylate of ter-butyl prepared in Example 680 compounds of Examples 693 and 694 were obtained in the same manner as in Example 691. Example 693 1- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-pipehdin ] -T-ylacetyl) -4- (4thfluoromethylbenzyl) piperazine [3425] Melting point 195-197 ° C (decomposition).

Example 694

1- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -T-ilacetyl) -4- (4Petition 870190039560, from 26/04/2019, p. 776/876

768/854 phenylbenzyl) piperazine [3426] Melting point 226-227 ° C (decomposition).

Example 695

Preparation of 4 - [(2,3-dihydro-6nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -1'-yl) -2-oxoethyl] (4-trifluoromethylphenyl) amide piperazino-1carboxylic [3427] 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] -1'-yl) -2oxoethyl] piperazino- Tert-butyl 1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (10 ml) was added to the solution, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride (1 ml) and triethylamine (1 ml) were added to the solution, followed by stirring at room temperature for 5 minutes. The solution was concentrated under reduced pressure, and the residue was dissolved in DMF (10 ml). A mixture of 4aminobenzotrifluoride (0.17 ml, 1.33 mmol) and 1,1'-carbonyldiimidazole (220 mg, 1.33 mmol) and DMF (5 ml) stirred at room temperature for 3 hours was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 200/1) and crystallized from methylene chloride-isopropyl ether giving (4-trifluoromethylphenyl) 4 - [(2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -1'-yl) -2oxoethyl] piperazine-1-carboxylic acid amide (213 mg, 59% yield) as a white powder.

[3428] Melting point 153.0-155.0 ° C.

Example 696

Preparation of 2- {4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -1'yl) -2-oxoethyl] piperazin- 1 -yl} -N- (4-trifluoromethylphenyl) acetamide [3429] 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] - Tert-butyl 1'-yl) -2oxoethyl] piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67

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769/854 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (10 ml) was added to the solution, followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride (1 ml) and triethylamine (1 ml) were added to the residue, followed by stirring at room temperature for 5 minutes, and then the solution was concentrated under reduced pressure. The residue was dissolved in DMF (10 ml). 2-bromo-N- (4trifluoromethylphenyl) acetamide (207 mg, 0.73 mmol) and triethylamine (0.28 ml, 2.0 mmol) were added to the solution, followed by stirring at 100 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 100/1) and crystallized from methylene chloride-diisopropyl ether giving 2- {4 - [2- (2,3-dihydro-6nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -T-yl) -2-oxoethyl] piperazin-1-yl} -N- [ 4trifluoromethylphenyl] acetamide (275 mg, 75% yield) as a white powder. [3430] MS 552 (M + 1) ⁺ [3431] Melting point 133.0-135.0 ° C.

Example 697

Preparation of 2- [4- (benzoxazol-2-yl) piperazin-1-yl] -1 - (2,3-dihydro-6nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidin] -1'-yl) ethanone [3432] 4- [2- (2,3-dihydro-6-nitrospiro [imidazo [2,1-b] oxazol-2,4'-piperidine] -T-yl) -2oxoethyl ] tert-butyl piperazine-1-carboxylate prepared in Example 653 (227 mg, 0.50 mmol) was dissolved in methylene chloride (5 ml). Trifluoroacetic acid (5 ml) was added to the solution, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride (1 ml) and triethylamine (1 ml) were added to the residue, followed by stirring at room temperature for 5 minutes, and then the solution was concentrated under reduced pressure. The residue was dissolved in DMF (5 ml). Triethylamine (0.21 ml,

1.52 mmol) and 2-chlorobenzoxazole (86 μΙ, 0.76 mmol), followed by stirring at 80 ° C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with

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770/854 methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was crystallized from methylene chloride-ethyl acetate giving 2- [4- (benzoxazol-2i) piperazin-1-yl] -1 - (2,3-dihydro-6-nitrospiro [imidazo [2,1 - b] oxazol-2,4'-piperidin] -1 yl) ethanone (99 mg, 42%) as a light yellow powder.

[3433] MS 467 (M ⁺ ) [3434] Melting point 260.0-263.0 ° C (decomposition).

[3435] Compounds obtained from appropriate starting materials, in the same way as in Examples 1 to 697 above are shown in the following tables from 26 to 77.

Table 26

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Example Kl R2 R3 K4 B5 K6 R7 PffC) 698 •H •H •H •H -CH, Ή Η 193-195 699 -H •H •H Ή -00.0½ Ή Η 195-197.5 700 •H -H •H •H • OCH, • Η • Η 139-190 701 Ή Ή -H -H -The -d • Η 182-183 702 •H •H •H •H •H -Η -Η 185 * 185 703 -GE, -H -fí -H -OCH, -Η -Η 177.5 * 179 704 'CH, Ή H -H -F • Η • Η 194-19S 705 ’ -CH, -H -H -H -CH, • Η Ή 146 * 147 70S -CH _S -H H -H -H -α • Η 190.5-192 707 -CE, -H •H •H  -H Ή -α 163-164 70S -CH, •H- -H -H  -H • Η -OCH, 177-180 709 • CH, •H •H -H -H -CF, • Η 182 183.5 710 -CH, -H Ή -OCH, -OCH, -OCH, -Η 179 * 132 711 -CH, -H -H -H ' -H Η -F 142 -144 712 -CH, •H -H •H • Br • Η • Η 197 199 713 -H -H •H -COKH, Η • Η 294 * 235 dee 714 -CH, -H •H •H • co, cyi, • Η -Η 151 -152 715 -CH, -H -H H -COCH, Η • Η Ι96Ί99 716 -CH, •H •H *H • SOJSIH, • Η Ή 218 220 71T • CH, •H •H •H -H Η 112 * 114 . 713 CH, *H •H Ή -H -Η 132-134 719 -CH, • CH, •H •H • Br • Η • Η 132 133 720 -CH, •H Ή • Ξ • CF, • Η Ή 198.5 * 200 721 -CH, -H -H -Ή • OCF, -Η Η 163.5-164 A 722 * ÇH » -CH, •H •H • CF, -Η • Η 129.180 723 -CH, -CH, H -H • OCF, • Η -Η 138-140 724 • CH, •H •H •H Morphblina- -Η -Η 223-225 725 • CH, -H •H •H Morpholine · ⁴ • Η • Η 134-135 726 -CH, H H -H CíHnJTHCO -Η • Η 197-198

Table 27

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723

729

780

731

732

733

734

785

738

IC cycle «H _u • CHiPh - (CH ^ Ph -qpckrCjHji -4 *; Piri <liia

-CHtCOí ^ H, -ch _b - (CH ^ COAHi -CHiCKjQ

737 ’C« H »

187-188.5

Ul * 142

124-127

176 178

151-153 (dee)

163-165

142 -143

129 r 130

94-96

DMSO'd *. 1.59 (8¾ a), 3.22-3.33 (2¾ m), 3.57 (2¾ t, J = 6.0Hz) _i 4.07Ϊ2Η, dd, J = ll.lHx, 27.6Hz), 4.27 (2¾ dd, J ~ 7.6Hz, 9.BHs),

6.47- 6.59 (1¾ w), 8.18 (1¾ s)

DMSO * d6, 0.65 (3¾ i, J «6.9Hz), 1.001.45 (12¾ in), 2.90-2.98 (2¾ m), -4.06 (1¾ dd, J ** 6.fiHz, 1Q.8H ^, 4.25 -4.46 (3¾ m),

5.48- 5.66 (1¾ in), 7.23 (1¾ t, J * 5.6Hz),

738

8.13Í1H, s) 739 2 -Η CH _: < 86-68 740 2 -0¾ Pk · 183-133 741 2 -CH, PhCHj- 127-127.5 742 2 -0¾ PhCHiCH / 124-125

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Example IR R2 R3 R4 £ 5 R6 R7 .pro· 743 -CH * -CH, • H * H -Η -The •H 103-104 744 -CH, -CHjPh • H -H -α Ή •H 16616TH 745 -CH, * C * H _U -H -H -Q •H -H 96-100 746 CH, -CH, -H * H • Br •H Ή 147 -150 747 -CH ₍ -CH, • H -H -CF, Ή •H 140 -141 748 'OHj 'CH _a • H -H -F •B -H 111 - 113 749 -CH _S here Ή Ή 'Cl -H -H 114 116 750 -ÇH, HERE. Ή Ή 'Cl -H .-H 67-89 751 • CH, • CACHÍCH »)» Ή · Η •The -H •H  161-165 753 CH, 4- <3PhCHí * -Η · Η -Cl -H -H '177 178

Table 29

Example IR R2 PIFC) 753 • CH _$ 4-CFjOPh- 165 166 754 4-CH ₃ OPh- 155 -157 755 ‘CH, 4'CIPh · 157 * 158 756 • CHj 3'GFaPb · 100 101 757 ‘CH, 4-BrPh * 168 170 758 ‘CH, 4 * FPh * 151 * 154

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Example RI R2

PffC) ‘

769

760

761

762

763

764

765

766

767

768

769

'CH, 4-CFePlr 151-155 'CH _to 4'ClPh · 143 - 144 <H _S 3'CLPh * 136 -138 -CH * S. ^ CljHr 142 -143 -CH ₃ 4-CH _at 0Ph- 163 -164 -CH ₃ 3-CFePK- 105-107 -CH, 4-FPK · 139 -140 'CH _S 4 ^ CF, OPhCH _t OCO 166-167 -CH, 4 ‘ 186 -188 CFsPhCH = CHCH _to OCO- -0¾ 4-CF ^ hOH, · 205-206

-CH, 4-CF _to 0PhCHf 133 -134

Table 31

Example RI R2 PífOOUlHNMR 770 • CH _at 4-CIPh- 228.8 - 232.2 711 • CH, 4 * CF, 0Ptr 236.2 - 237.4 772 -CHâ 4-CF * 0PhCH, · CDOI ,; J.76 (3H, á _f 3.03 (4H, tó, 3.62-3.67 (4Η, 'ιη) _φ JjOKIS, d, J = aa2Hi), 4.O4Í1H, d. 4.13 (1¾ d, J »10.2EL ·) 4.48 (1¾ d, J = 2O.2Hs), 5.15 (2¾ 5.76 '6.SÚ (2H. M). Αΐ5-β.Β9 (2Η, m), 7.18-7 ^ 3 (2¾ nü, 7.3B7. 42 (2¾ m), 7.54 (1¾ ¢) m 'CH, 4-CIPhCH, · 174.2-175 YOU • CHj J-CFjOPhCHíOCO- 155.5 * 156.5 775 4- -CH. CF ^ hCH ^ CHCH ^ CO * 155 -159.8

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Table 32

Example R2B3 R4 R5 Re PfÇVl · 776 • CH _f • H -H * H  rH -Η 151 * 153.5 777 CH _t Η Ή -I * H -Η 220221 77S OH » • Ή · η · α -Η '.- Η 185 · 186.5 779 -CH, Ή Ή Níorfòlina > · Η * Η 236 - 240 dec -780 • CH, Ή · Η Piperedino r -Η -Η 217 * 218.5 dec

Table 33

Example- R1 R2 R3 R4 PffOOU 1HNMR 781 CH, -Η -H -CH, 230 - 231.5 8 « 782 -CH, -Η -CI 'CH, 201 -204.5 dec 738 • CH,. _H -H 4-CF ^ h- 258-259 iec 7B4 • CH, -η -M 4-OPhCH, - 207 - 208.4 785 -CH, Ή -H. 4-CSPli · 251-257 dec 786 -CH, -Η -H CH.CO- 206 - 2C7.5 787 Ή <1 Ο ^ Η, ΟΟΟ- 168.5 171 788 ’ • CH, -Cl -H t-BuOCO- 192 · 1S-L5 789 -ch, -ci -a cya, ocb- 178.6 -130.5 790 -ο®, -a -a-Buoco- 233 - 233.S dec 791 -CH, -Ci -ci 224.2 - 225.7 792 -CH, - _H , _H -cOjCHjCF, 213 216 793 -CH, -Η -H -COjCH, 197.S 199 794 -CH, -Η -H -COjtCH ^ CH, 198-201. 795. -CH, -Η Ή -CO. (CH.), OCE, 176 -179 796 -CH, -H -Cl 4 * CF, OPhCH ^) CO · 153-155 797 -CH, -Cl -H 4-CF, OPhCH, OCO- 176-176.3 793 -CH, -Cl -a 4-CF, CPhCH _t OCO · 196.6-197.5 799 -CH, -H -H 4-0F, OPhCH2OCO- 137 -139 800 -CH, - _H -η 4-C?, PhCH, OCO- 130.6 - 182.5 801 -CH, 4- -H -H CF.PhCE-CHCHjOCO- IBS -187 802 • CH, -Η -H 3,4-CI ₃ PhCHJX! O · 171-171.5 803 • CH, -Η -E 4-CT, OPhNHCO- 228 - 232 dec COO,: 1.76C3H 2.30 (6H. I>, 2.61 (28, t, J = S.BH ±), 2.99-3.04 (4H, m), 3.60-3.64 (4H. M), 4.03 (111, d. J = 10Hx>, 4.04 (1¾ d. J ^ 10.OlHs), B04 • CH, -H -H -CO / CHiljNiCH ^, 4.18CIH, d, J-ΙΟ.ΐΗώ, 4.22 (22, t, J-5.8Hz. \ 4.49Í1H, d, J = J0.2Hz), 6.76-6.Í1C2H, m), 6 ^ 3-6.89 (2¾ to), 7.55 (1H, s)

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Table 34

Example BI Έ2 K9 PIT0 8Ό5 'CE _S -CH ₈ 4-CF _to OPh · 127.2- 129.7 806 'GH,' CH, 4-CFiPh- 131.5-183.6 807 * CHj -CH, 4-N’CPir 149 152 808 'CH, * CHy 4CFjOPhCHjOCO 84.2- 86.8 808 -CH ₃ -CH, 4-OPhÇHiOCG- 116.2'116.6

Table 35

Example RI R2 PffC) or H NMR βίο -CT ₃ -OPh 153.2-154.8 CDC1, · 1.18-1.42 (H2H, m). 2.61 (3H.e). 1.87-2.01 (2Η, κΰ, 2,312.60 (8Hpn), 2.78-3.02 (411, = 0.3 J4-3 J0 (1H, hey). 611 • CH * 4-CFjPbNH · 3.82 (1H, d, J = 3.1 Hz). 3.91ÜH, d, J = fl.7Hi), 4 ^ 3ÜH _t d.Js4.7Hd, Ô.54 (2H, dJ-B.6Hi), 6.98- 7.86 (2H.dJ => 8.6Hz), 7.54 ( 1H, a) 813 -CK, 4-CF, Ph- 130-131.8 813 ⁴ CHg aPE UHj * 117.6 - 11S.5 814 -CH, 4-QPhCHr 146.5-147.5 816 -CH, 4'CLPhCO * ' 177 179 816 • CH »4-CP _l PhQQ- 95 -100 817 'CH. ^ - CFjOPHO · 119.4 120.7 818 -CH, 4-CiPhO- ’ 141 -144 81 » -CH, 3-CF ^ hO- 39 - 91.7 820 CH, 4-NCPhO · 171-174.7 821 -CH, 4-FFhO- 124 ’128 822 -GHjrc ^ opãCfí.o- 118 -115 828 -CH, 4-ClPbCH, O- 138 -140 824 -CH, 4-PhPnCHjO · 215-116.6 826 • CHjPhCHjCH.O 79-81 826 CH, 4-.PyridylCHA «0.3 --83.9 827 'CH.3 Pyridyl-CHA 77-79 828 -CHiá-CFtOPhCH ^ OCO 101 102 829 -CH, 4-OPhHHCO · 153 -165 aso CH, 4-CIPhCH ₂ NHCO- 161 164 «31 -CH, 4-ClPhNH- 159-161 832 -CH, 4-NCPhNH · 148.5 ’150 833 ’CHi + ClPhNfCH,) ' 180.2 · 181.1 des 834 • CH, 4-NCPhN (CH,) · 188.5-191 835 CH, 4-CF3PhNtCH ^ 161 154 836 CH, Ü-OPliÃN- 178.5 - ISO

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Table 36

R3 R4 R5

Example RI H2

837 CK, -H 838 -CH, -E $ 33 -0¾ Ή 840 -Η -H 841 -CH _S -H 842 -0¾ -H 843 -0¾ -H 844 -0¾ * Jí 845 -CH _to -H 848 -0¾ -H 847 -CH * -Ph 848 -CH, -H 849 -CH * -H

-H- -ΟΗ (ΟΗΛ -B -C2 -α • Η •H -CF, Ή -B CF * -Η Ή -OPb -Η -00¾ OCHj ΟΟΗ. -Ή -COjCH, • Β • κ ‘8-Piridíh Η .-Ph Η -Η -Η Cycle'C * Hu • Η • Η -Η -Η • Η -CH = GHFh • Η • CF, • Η • CF,

R6 PifC) OUlHNME

-Η 158.5 -160 -Η 115 -117.9 Ή 126 1202 -κ 164-166 -Η 157 -158J -Η 147 · 151.8 -Η 151 - 252.5 -Η 140 143.8 -Η Μ.6-9 & 5 • Η '162 · 163.9 • Η 146.8 -149 -Η · 178.5 -1818 Η 154-156 ^.

850 'CHj Ή

851 -CHj -H

352 -0¾ -H 853 -CH, -H

• Η ΟΟΗ, -Η -Η • CHjPh Ή

CDO _S 159 (3H, ·), 2.34 (42, bs), 2.C0-2J9 / 22, m), 2.53 (12, d. J = 14.eHz), 2.67-2.76 / 22. m).

„2J35C1H, d, JdX.SHz), 3.41 (12. ^N d, J =» 12.9Hz), 8.47 (12, d, 'J-12 ^ H =), 9.87 (12, d, 3 = 9, SHÚ , 4.30 (1¾ d. J = 9.6Hz). 7.23 · 7.33 (52, m). 7.53 (lKa) CDQ * 1.58 (32, «>, 2.30 (42. br). 2.49-2.57 (2¾ m), 2.52 (12, d, .1 = 14.9¾ 2.65-2.73 (2¾ m), „2.84 (12, d, J-14.9Hz), 2.83 (62, ' ⁿ a), 3.34 (2H , d, J-3.5CHz), '9.86 (12, d, J = 9.5Hz), 430 (12, d, J> = 9.6Hz). 6.67 (22. d, J'& 7Hx), 7, 11 (22, d, J = 6XHà _t 7.52 (12.4} CDCU 1.58 (32,), 2.31 (42, hr), 2-5O2.68Í2H, m), 2.53 / 12, d, J = 14. & Hz), 2.66-2.74 (22, »). 2.64 (12, d, J = 14.6Hz), 3.35 (12, 2 d,> 18.0Hz), 3.41 (12. D, J-13.'0Hz). 3.79 (32, s), 3.88 (12, d, J-9.7HU 4:30 (1¾ d. J = 9.7Hz), 6.83 (22, d, 3 = 8.62 ·), 7.17 (22, d, J-8.6 Hz), 7.52 (1¾ b) CDCtj 1.61 (32, i), 2.30-2.73 (92, μ), 2.84 / 1H. D, J = 14.8HI), „3.49 (22.3), 3.67 (12.4.3 * 9.7 Hz}, 3.9512H, e), 4.30 (12, d, J = 9.7H2), 7.09-1.33 / 9H, m). 7.52 (12, SY

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Table 37

Example Ri R3 R4 RB RS ~ ~ ÕUiH Nbffi

854 -CH »-Η -H -d -H -H 176.8 - i & i.a 655 • CH, -3 -H -Cl -d -3 111.8 -114.8 866 -CR, -H -H -0CH _t -Η Ή 183.3 * 186.6 857 -CH, -K -3 -3 • 3 -Cl 123.5 125.3

CDCLÍ 1.69 (3 «i), 2.37 (43.1«), 2.51-2.61 (2 «ml

858 -GH »-H Η Ή -Ή -H 868 -CH, -H • H -CF, • Η -H 860 CH, -H -H -OCF, -Η -3

2.54 (1 «d, J = 1OH« 2.69-2.76 (2 «m), 2.96 (1« d. J-14.eHz). 3.44 (1 «d. J = 13.UL ·), 8.51 (13, d, J = 13.1Hi), 3.86 (1 «ã. J = $. 6Hs), 4.31 (1« d, J = 9.6H3), 7 ^ 9-7.36 (2 «ca) 7 ^ 9-7.47 (23 , m), 7.51 · 7.6 0 (4Hj '), 7.53 (1 «3)

CDC1,: L60 (SH. ·), 2.37-2.76 (83, m), 2, »7 (13, d. J» 14.9Hz), 3.49Í2H, 3) ,. 8.83 (13.4. J = 6.6 Ha), 4.30 (1 «d. Je.SHi), 7.37 (1« d, 0 = 6.03 «7.53 {1H. E), 7.64 (13, d, 0 = 3.031), 7.63 (4« a)

CDCU; 1.60 (3 '*), 2J3B43, br), 2.55 (13, d, J-14.9' z), 2.60 (23, br). 2-71-2.76 (2 «¢), 237 (1« d, J »14.9Hz), 3.50 (2« »), 3.89ÜH, d, J« 9.7H «4.60 (13, d. J-9.7H «7.27 (23, d, 7.36 (23, d, 0 = 3.1), 7.47 * 7.52 (2« »!), 7.53 (1a), 7.55-7.61 (2« p>)

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Table 38

IR

PTO

134 -133.3

831

188.8-190.7

882

863

127 -131.5

156 -156.6

864

102.8-104.9

865

866

129 ’133

867

164.0-168.5

868

221.6 - 222.3

N

869

158 * 159.4

870

105 · 107

871

142 -145.4

HLC °

Example RJ

-Ch

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Table 39

Table 40

Rí H3

Example EU K2 R3 RX R5 R6 PffC) or IS NMR 876 * H 'Η -H * CF, -Η Ή 175.8 - 1766 877 • CH, Ή -K -H Ή -Η -180.6 164L2 878 -CH, -Η -H ’F -Η -Η 175 - 179.5 879 • CH, -Η Ή OCH * Η Η 172 -172.5 880 • cs, · η -h -co.cn, -Η -Η 175 179.2 eex CH, Η -H -CH, -H -Η 165 - 185.5 882 -CH, Ή Ή -Cl -α Ή 177 -177.3 883 -CH, Ή Ή * H - * CF, -Η 171.6 * 173.6 844 -CH, · Η ‘Η · Η • Η • CF, 179.6 * 180.3 885 • CH, -Η -Η -CI CF, • Η 170.5 -171.2 888 -CH, -Η · Η -CO3 -Η Η 243-252 B87 -CH, ‘Η Ή -Η -Η 191 * 192.2 888 -CH, Ή -Η -N (CH ^ Η -Η 205 207 889 Ή Ή -Η -F -Η Η 1Τ8.5 - 179.5 890 Η · Η * Η -CN Ή Ή 211 - 211.5 891 • Η Ή Ή -CI Ή Ή IS 3 * 133 -, 5 CD Cl,. * 1.M.CJH.i), 2.59-2.75I2H, mJ, 2.62 (1H. d, Jsl5Hi), 2.90-2.95 (2H, re), 2.93 (1H, d, 892 -CB, Ή -Η -CF, Η -Η J = 15Hd, 3.00-3.25I4H. m), 3.94 H, d. J = 10There are, <3 & (1H, d, J = 10Hi), 6.B6I2H, d, J = 6Hi). 7.49 (2¾ d. J = SHá _t 7.53 (1¾ 5) 893 Μ '· ^Η - »co, c (chj,' ^h • Η 198.5'200.5

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Table 41

Ο

£ 5

Example Kl R2 R3 Η4 R5 R6 TÍTC). 694 -CH _a H •H -α Ή -H 144.2 -145.6 695 • CH * •H •H • OCF, -H •H 158 156.9 896 'CH, H -H α The -H 114.5 · 116.6 697 • CH * • Ή H -Η -The -H 132.4 * 136.3 698 -CH, -H H -Η -H -Cl 143.5 145 899 -CH * •H •H -Br •H •H 151 152 900 • CH * -H •H • Ph -H -H 134-135.2 901 -CH, -H -COtCH, •H -H 127 180.5 902 -CH, •H -H -OCH, -H -H 128 -180 903 • CH * •H •H • OOHjPh -H •H 128 131 904 -CH * • Cl •H •H •H -Cl 142 - 145.5 906 • CH * •H -Cl •H -The -H 132 · 135.3 906 -CH * •H •H •H • CF * •H 117 * 118 907 uXl | •H •H. -CH, •H Ή 117 * 118 908 -CH, -H •H -H -OCH, Ή 106-108 909 -GH, -H •H -H -H -CM, 143 * 145 910 -CH * -H -H . Ή -H -OCH, 127 130 911 • CH * •H •H •H •H CF, 144 145 912 • CH * •H •H • OCJi, H H 126 127 913 -CH * -H -H •AT THE* -H •H 156 158 914 • CH * •H -CF, •H • CF, -H 159 160 915 -CH * Ή •H -ON -H H 125-129 916 -CH * •H •H • C (CH ^, -H •H 147 149 917 -CH * -H -H -H • CH, -H 125 127 918 • CH * -H -H -CH * • CH, -H 135 138 919 -CH, -H •H -OOH, -OCH, -H 149-151 920 • CH * -H •H H 131 133 921 -CH _a -H •H -α, Η, -H •H 144 146 922 • CH, •H •H • SO, CH * -H -H 112 115 923 • CH * -H •H • CONiCH ^, •H •H 108111 924 -CH, •H • Ή • ΟΟΝΗΟ, Η, •H -H 124126 925 -CH, •H •H -OCHÍCHík -H H 122-123 926 • CH, -H Ή • ΟδΟ, ΟΗ, •H •H 100 104 927 • CH, -H Ή -I -H -H 132-134 928 -CH, -H -Η -KHCOCH * -Ή •H 105 · 109 929 • CH * •H • Η • CONHj • Ή •H 159 -161 930 -CH, -H -Η -F • Cl -H 148 -149

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Table 42

Example RI R2 R3 R4 R5 R6 PfÇC) or 1HNMR

CDQ, 1.62 (3¾ a), 2.38-2.70 (4¾ tn), 2.56 (1¾ d, 187 (15, d,

3 = 14. ° Hz), 3.41 (4¾ ta), 3.92 (1¾ d,

3 = 9.7¾¾ 4 ^ 3 (1¾ d, 3 = 9.7¾¾ 5.06 (2¾ a), 099'7.07 (2¾ an), 7.28-7.34 (2¾ m), 7.53Í1H, e) CDC1 »1.62 (3¾ a), 2.45-2.75 (4¾ bxn), 2.58 (1¾ d, J = 14.9Hz), 2.86 (1¾ d, J = I4.9H =), 3.20-8.60 (4¾ hr}, 3.94 (1¾. D? 3 = 8.8¾¾ 4.29 (1¾ d, 3 = 9.9Ηώ, 5.15Í2H, a), 7.44 (1¾ d, 3 = 8.011¾ 7.54 (1¾ e>, 7.61 (1¾ d, 3 = 8.0¾) CDCJ, 1.59 (3¾ a). 2.30 -2.70 (4th ra), 2.56 (1¾ d, J = 15H, 2.96 (1¾ d, 3-15¾¾ 3.10-3.55 (4H, m), 3,910¾ d, 3 = 10¾¾ 4.28 (1¾ d, 3 = 10¾¾ 5.03 ( 2¾ a), 9.30 (1¾ bra), 084 (2¾ d. J = 6Hz), 7.24 (2¾ d, 3 = 6¾¾ 7.53 (1¾ s) QDCU LAW (3¾ a), 2 ^ 5-2.70 (4¾ m), 2.56OH, d. (1 = 15¾¾ 3,950¾ d, J «15Hx), 8.05-3.33 (4¾ nJ, 3.690¾ W, 3.91 (1¾ d, J = 10HA 4 ^ 8 (1¾ d, 3 = 10¾¾ 4.98 (2¾ e), 055 (2¾ d. 3 = 9¾¾ 7.14 (2¾ d, 3 = 63 ^, 7.53 (1¾.) 114-115 124 · 127

931

932

933

934

935

936 • CH.

CH,

-CH,

H • H

-F * E • H

-H

-H

H

-H

-THE

NH,

-H

-Ή

-H

-H ’-H (CH ^ CiGH ^ tSi (CH3.COCONH • H -B

-H -H

Table 43

Example R1 R2 PfiC ° C) 937 - (CHjjPh 143.5 - 144.6 938 -CH, d-ClPhfClOr Π8- 119 939 -CHj 4-ClPhCH-CHCH) · 221 - 123.3 940 -CH, 4'CF _! ^ hCH = CHCH ₁ ' 121 - 122 941 -CH, 4 * CFaOPhCH ^ CHCHr 127-128

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Table 44

Example: Kl 12 E3 R4 B5 56 PffC) 0U1HNM5 942 • CH, -H -H -H • Cl •H 83-65 943 -CH, -H -B -F -H -H 174-175 944 • ch ₅ -h -h -H •H -CH, 187 - 1B8.5 945 • CH, -H. -H -H •H •B 163.5-166.5 946 -CH, -H -H • Cl •H -H 172.6 · 174 947 Η Ή -H -OCF, -B •H 128 -129 948 • CH, -Η -H -d •The •H 97 - 98 949 • CH, -Η -H -F -F •H 115 -116 950 • CH, -Η -H ,-H • F • F 101-103 951 • CH, -H -F -H • F •H 85-87 952 • ch; -f -f • F -F • F 143 -144 953 -CH, -F -H -F •H • F 92-95 954 -CH, -H ’-F -H •B F 144 -146 955 -CH, -F -H -H -B •P 169 -170 956 -CH, -Η -H • F -H • F 178 -182 957 -CH, -Η -H -H • F •B 112 -115 958 • CH, -Η -H -H -CF, •H 76-80 959 -CH, -Η -H -H -H -P 175 176 960 -CH, -Η -H • Br -B •H 166 * 167 961 • Η -Η -B • F •B •H 12LS * 122 »62 -Η -Η -H -H H 112.9 -116.7 963 • Η -Ή Ή •The -The H 105.5 -106 964 • H -Η -H -H • Cl ' •H 97.5 - 98 965 -St -B · -H -H • F •H 93-94 966 • CH, -Η -H -OCHF, -H -H 134 -135 967 -CH, Ή -H • F • OCH, • F 71-74 968 -CH, Ή -B -F -OGBF, -F 84-86 969 -CH, -Η -H • Cl • OCHF, •H 85-87 970 -CH, -Η -H -The •H •H X30-181 971 -CH, -H -a CF, -H -H 185 -187 972 -CH, -Η -H • OCF, -H -H 172 -173 973 -CH, -Η -B OCHfCFt -H B 76-60 974 -CH, -Η -H •The OCHtCF, -H 139-140

Table 45

lExamplei R1 R2 R3 R4 Rfi

975 • CH, -Η Ή -OCHjCF, -The 976 • CH, -H -H -OCHF, -Cl 977 -CK, -H * H -Br • OCHF,

P-6 PfÇC) m 1HNMR

CDC1, 1.62 (3¾ s), 2.40-2.75 (4¾ tr.), O7 (1H, d, J-15HD, 2.βΤ (1Η, d, J = 15Hz \ 3.05-3.50 (4¾ m).

„3.92Í1H, c, J« 10H =), 4.28ÍLH, d, J = 10Hs), ⁿ 4.40Í2H, q, J = 8Hz), 5.02 (2H, »), 6.40Í2H, d, J = rSHz), 7.21 (2¾ dd, J ** 8.2H. 7.39 (1¾ d, ί = 2Ηώ, 7.53 (1¾ s) CDC1, 1.62 (3H, s), 2.40-2.70 (4¾ ra), 2.58 (1¾ d, J = 15Hz), 2.87 (1¾ d, J => 15Hz). 3.10-3.55 (4¾ m), • H 3.96 (1¾ d, J = 10He), 4.30Í1H, d, J = 10Hi, 5.13 (2¾ ), 6.53 (1H, t, J = 733á, 7.10-7.30 (2¾ _TO ), 7.42 (1¾.), 7.55 (1¾.)

CDC1,1.62Í3H, · s), 2.40-2.65 (4¾ m), 2 ^ 9 (1H, d, J = 15Hz), 2.86 (1¾. D, J = 15HJ, 3.00-8.50 (4¾ m).

• F 3.96 (1¾. D, J = 10Hr), 4.29 (1¾ d. J = 10HsJ, 5.14Í2H, »), 6.59 (1H, t, J = 73Ez), 7.17 (1¾ m). 7.39 (1¾ m), 7.55 (1H, e)

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Table 46

Example R1 R2 R3 R4 Kfí RE PffC) 97S • CHj •H -H • CF _a •H -H 189.8 141.7 979 •Tea •H •H •H • d •H 108111 980 -CH _a •H •H •H •H •Tea 185 -186 981 'CH _S -H -H -Cl -CF, -H 115 115.5 982 • CH, -H -H • cf ₃ -CH, H 91-91.5 983 'Tea -H H -SCFs -H  Ή 136.5 - 137 984 ‘CH, • Ή •H • F • Cl •H 72.5 - 73 985 CH _S *H Ή • Cl -H • CH, 178.5 * 179

Table 47 wo

Example IR ' LOL PffC) 966 • CH, ’ÇH ^ CYCL 101 · 103 987. -CH, Cycle'C ^ iu 189.fi191.6 983 -CH, -CHtCF, 128.5 124 989 • CH, -CHjCH-CÍCHÍs 138-138.6 990 -CH, CE) -3.4-a, PhCH = CHCH, · 145 146 991 -CH, (E) -4-CIPhCH = CHCH, - 124-125 992 -CH, CEH-GF, OPhCH = CHCH ₃ · 60 * 61 993 -H CEH-OlPhCH-CECH, - 113 -114 994 -H' (EH-ClPhClCH ^ CHCH, · 109-110 995 -H QH-ClPhCCCH ^ CHCHf 95-96 999 CH, ffi} -4-CFjPhGH-CHCH, - 132 133 997 -ÇH, Ca-t-CP ^ hCH ^ CHCH, - 136 -140 998 -CH, (E) -3-CF, -4-C!? HCH = CHCH.- 147 * 149 999 -CH, (E) -4-FPhCH = CHCH.- 155-166 1OOO -CH, 122-123 1001 -CH, (í-CFjPtójOCHCH, - 145 146 1002 • CH, 4 · ΟΡΜΟΗλ · 150-161 1003 -CH, 4-aPhíCHj), - 96-97 1004 • CH, 4C! Ph (CH ^ _< - 76-82 1005 -CH, 4-apho (cíy, · 138 139 1006 -CH, 4CF, OPh (CHJ, - 46-48 1007 • CH, 4-CF, Ph (CH ^ _t - 116 120 1008 -CH, 4-CF ^ hO (CH ^, - 104 · 106 1009 -CH, i-GFsOPhNÍCH ^ CH,), · 102-104 GDC1, 1.62I3H, s), 2.02-2.10 (3H, m), 2.67I1H, d, J = 14.9Hi), 2.40-2.73I4H, m). 1010 • CH, ®) -4-CWC (CH> CHCH2 · 2.87 (1H, d, J = 14.9Hz), 3.06-3.62 (4H, m), 3.93C1H, d, JS.7HÓ, 4 ^ 9 (1H, d, J-9.7Hz}, 4.76 (211, m), 6.87Í1H, dü J-1.3H », 6.7Hz), 7.23-7.37Í4H, m), 7.S4 (1H, *) CD®, 1.62Í3E, s), 2.02-2.10Í3H, m), 2.58 (1H.- d. J = 14.9 &>, 2.95-2.72Í4H, m), 2.86Í1E, d, J = 14.9Hz), 3 , 04-3.66 (4H, m). 1011 -CH, (2) -4-CJPhCCCH> CHGH2 · 3.94C1H, d, J = 9.8Hz), 4.30C1H, d, J = 9.EHz),

4.46Í2H, m), S.66 (1H, dt,> 1.4Ha, 7.0Hz), 7.04-7.12C2H, m), 7.23-7.35Í2H, m), 7.53 (1H, 3)

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Table 48

1012

-85

1013

120 -140

1014

O

189 ’190

1016

1015

-Ch

1020

196.1- 199.1

137.4 ’139.2 · 76.4

121.1-122.1

177.1 - 178.9

158.5 160.4

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Table 49

Example Ri 'R2 PflfC) ►

1021

1022

1023

1024

1025

1026

193.4 - 195.9

Cl

203.6-204.9 α

Cl

185.2 -187.5 • CH

N

215.3 - 216.4 α

O

89.7 - 91.8

93.6 96.5

1027

1028

1029

1030

180.T -182.3

170.2-170.6

134.3 135.7

83-6 86.3

1031

191.3 192.9

Cl

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Table 50

PffC) or 1HNMR

174.3 - 179.2

108.9 118.1

193A1947

152 * 153.5

190.3 * 19L2

177.5 * 180.9

127.5 - mi

140- 141.5

1040

114 -117

1041

-Ch

Οθσΐ ₄ 1.40Ί.62 (5Η.πι \ 1.80-1.93Í2H, br) _t 2.46 '2.64 (130, m), 2.87 (10. D. J ~ 14.9Hz). 3.37Í4H, br), 3.92Í1H, â, J * 9.7Ha), 4.20 (20, t, 2 * 6.1}, 7.53 (10, a)

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Example R2 PIFC) 1042 -CH, 4-CF _s OPh ' 150.5181.4 1043 * CH _t 4-CP ^ h · 153.6 -160.6 1044 ‘CH, 4-CH »OPh- 138.5 139.5 1043 -CH, Ph- 163 · 163.5 1046 • CH, 4-FPh- 159 160 1047 -CH, PhCHf 141.5 -142 1048 'CH, 4-OPh- 177 - 178 1049 4-NCPh- 158 - 159 1050 -CH, 4-CIPhCH, - 144 145 1051 -CH, 4-C? A'hCH _í - 95.5 · 97 1052 V £ La 4-CF.QPhCHr 143 -148.5 1053 -CH, 4-CF ^ PhCO- 160.5 - 162.4 1054 -CH, 4-OPhCO- 218 - 220.3 1055 -CH, 4-CF, OPhCO- 169.8 -172.7

Table 52

Example R1 R2 R3 R4 R5 A6 PfTC) 1056 -H -H -H -cf ₃ •H -H 215.3-217.8 1057 Ή -H -H -Br -H -H 219.2-221.3 1058 -H -F -H -H -H 198.8 * 200.5 1059 -H Ή • F • Cl -H •H 99-199.5 1060 -H -H -H -CN -H •H 180.2-164.1 1061 -H -F -F -F -H -H 1BB.5-1B9.2 1062 -H *H . -F • F • F -H 191.7-192.6 1063 -H • F -H -The Ή •H 202.8-203.3

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Table 53

Example i R1 R2 R3 R4 R5 R6 PflX) 1064 -H •H 44 -The -H -H 214.2 -214.0 1065 -H 44 -Cl -The 44 -H 204.1 -205.7 1066 -H 44 -CF, -H -H 44 127.8-131.8 1067 -H 44 -H -OCF, •H -H 204.2 - 205.3 1068 44 -H -H -F -H -H 199.2 - 200.2

Table 54

Example> R1 R2 R3 R4 R5

1069 -H -H * Cl -H -H 164 * 6-165.9 1070 -H -H -cf ₃ -H -H 194.9 -196 1071 -H -H -ocf ₃ -Η -H 211.7-212.1 1072 -H -H -H • CF, -H 182.9-1B5.9

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Example í R1 R2 R3 R4 R5 A 6 pre) 1073 -H -Η Ή -F -H -H 202.5 - 203.1 1074 -Η 44 -OCH * •H -H 205.4 - 206.4 1076 -Η • Η -Η -Cl -H -The 162.7-164 $ 107 -Η -Η -Η -Cl -H -H 233.7 - 236 ^ 1077 • Η -Η • Η -1-Pyridyl -H -H 249.1 249.7 1078 -Η Η -Η -Ph -H -H 211.6-212 1079 -Η 44 • Η -OCH _to Ph -H -H 202.2 - 203.9 1080 -Η • Η 44 -Br -H -H 224.4-226.2 1081 -Η -Η * Η -OC, H „ 44 -H 156.8-158.3 1082 -Η -Η -Η -CN -H -H 197.8-198.7 1083 Ή -Η Η -OPh -H -H 198.1-200.1 1084 -Η -Η -F -F -F -H 153.8'196 1035 -Η -CHg -Η • CH, -H -ch ₃ 177.9-178.3 1086 • Η -ch ₃ Ή -H -H -CH, 175.7-178.2 1087 44 -Η -CF _a 44 -CF> -H - 200 ^ -202.3 1088 -Η • Η -Η CJ. -H 197.2- 199.2 1089 • Η -Η • Η -Br -H -F 206.1 - 207.4 1090 -Η -Η • Η -F • F -F- 174-174.7 1091 -Η -Η -Η -Cl -H -F 202.6-203.7 1092 44 • Η -Η -C ₄ H, -14 44 162.2-165.1 1093 44 44 -Η 'N (Ph) _s -H Ή 182.6-186.4 1094 -Η Ή 44 Ή -Cl -Cl 223.5-224.5 1095 -Η • Η 44 -1 44 44 217-22U 1096 -Η -Η • Η • 1 - (1 r2, -4-Triazolyl) -H -H 200.6-202.3

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Table 56

Example IR R2 R3 R4 R5 R6 MS 1097 •H -H -H -H -H -H 370 1093 -H -Cl . Ή -H -H -H 404 1099 -H -H -Cl -H -H -H 404 1100 -H -F -H -H -H -H 338 1101 -H -H -H -CHÍCHJ, -H -H 412 1102 -H -H -H -AT THE, -H -H 415 1103 -H -CF, -H -H -H -H 438 1104  Ή H -CF, -H -H *H 438 1105 -H -H -H -C (CHJ _a -H -H 426 1106 -H -H -H -OC ^ -H -H 414 1107 -H -Cl -CJ -H -The -H 472 1103 -H • Cl -Cl -H -H -The 472 1109 -H Ή Ή -H • OPh 462 1110 -H -H -F -H +1 -F 406 1111 -H • F -H -F -H Hi 406 1112 -H -H -H -F • F •H 406 1113 •H -H -F -H -F -H 406 1114 -H -H -H -F -F 424 1115 Ή -H -F -H -F -F 424 1116 -M -F •H -H -F 424 1117 -H -H • F -F -H -F 424 1113 -H -F -H -F -H -F 424 1119 •H • OCF, •H -H -H -H 454 1120 -H -H -H • CíH, -H -H 398 1121 •H -H •H -H -Br -H 448 1122 -H -Br -H -H -H -H 448 1123 -H -H -H -H -F -F 406 1124 Ή -Cl •H -H -Cl 438 1125 -H -OCjH, -H •H -H -H 414 1126 -H -H -H -OC.H. -H -H 442 1127 -H •H -H Ή -H -OCHjPh 476 1128 -H -H -H -H -NO _t -H 415 1129 Ή -H -H -H -OCF, -H 454 1130 -H -H -H •The -Cf -H 433 1131 -H -Cl -H H -CJ -H 43 S 1132 -H -H -H -H -OCOCH, -H 423 1133 -H -AT THE, -H H -H -H 415 1134 -H -H -H -H -F -H 3SB 1135 -H -H -Cl -H -Cl -H 43B 1136 H -H -H -H -CN -H 395 1137 -H -H -OCH, -H -H -H 400 1133 -H • OCH, • OCH, -H -H •H 430 1139 -H -OCH, -H • OCH, -H -H 430 1140 -H -OCH, -H •H • OCH ;, -H 430

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Table 57

JW) ·

Example R1 R2 R3 R4 LOL R6 MS 1141 -H 44 -H -OCH, • OCH, •H 430 1142 -H 44 -H • OCH, -OCH, • OCH, 450 1143 -H 44 -The 44 -H -AT THE, 44 & 1144 -H -H 44 -OCH, -H -HO, 445 1145 -H 44 -OCH, -H •H -AT THE, 445 1145 -H -H 44 -H -ΡΪ1 44 446 1147 -H -NHSO, CR, -H •H -H -H 453 114S -H 44 44 -CH, -H -H 334 $ 114 -H 44 44 -CH, -CH, -H 398 1150 -H -CH, -H -CH, 44 44 398 1151 -H -H 44 -H -CH, 44 354 1152 -H -H -CH » 44 44 -CH, 398 1153 -H -H 44 -H -H • CH, 384 1154 -H 44 44 41 -CH, -CH, 398 1155 -H •H -H • OCOCH, -H -H 426 1155 -H 44 44 -OCJ4, -H -H 428 1157 •H -H 41 • NHCOCH, -H •H 427 1155 -H •H -CH, -H -CH, -H 398 1159 ,-H H -CH, -CH, 44 -CH, 412 1160 -H 44 • K -CO _} CH, -H -H 428 1161 -H -H -H -CHwCHPTifxans) •H 44 472 1162 -H 44 -N (CHJ, -H 41 Í13 11S3 -H 44 -Br 44 -H -OCH, 478 1164 44 44 -H -F -H -Cl 422 1165 -H 44 -Br -H 44 -F 468 1166 41 •H -OCH, Ή 44 -F 418 1167 -H 44 44 -CHjCHtCHJ, -H •H 428 1168 44 • Br -H • OCH, • OCH, *H 508 1169 -H -F • F -F -F • F 460 1170 44 44 -H -NtCHJ, Ή -OCH, 443 1171 -H -H -GCHjPh •H -OCH, Ph -H 582 1172 Ή -H •H -OCH ^ h -OCHjPh -H 582 1173 -H Ή -H -H -OGiHs -H 414 1174 -H -H •H 41 -OCH, Ph -H 476 1175 •H -H 44 • 0CH ₂ Ph • OCH, -H 506 1176 •H -H -H -SC, H _t •H •H 430 1177 -H 44 -H -OCHF, •H •H 436 1178 -H 41 44 -OCHjCH,), -H -H 428 1179 -H 44 -OCH, -Br -H 478 1180 -H 44 -H -N {C _} HJ, -H -H 441 1181 •H -H 44 -OCH, -F •H 413 Π82 -H •H •H -OCH, -CH, •H 414 1183 44 -OCH, -H •H • F •H 41S Π84 Ή -Cl -H H -AT THE, -H 449

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Table 58

Example IR R2 R3 R4 LOL R6 MS «85 -H 44 -H -OCJÇ -OCjH, -H 498 1186 -H 44 •H -OCOCH, -OCH, -H 458 1187 •H -AT THE, 44 • OCH, ‘ -OCH, 44 475 1188 •H 44 -H -SCH, -H -H 416 «89 -H •H -H -Cl •AT THE, -H 449 nso -H -H -H -SOtCH, -K -H 448 «91 -H -H 44 -OCH, • OCHjph 44 506 < 1192 -H -H -Cl -CF, -H 472 «93 -H 4 -H -H -H -H 496-- 1194 44 -H -H 44 -SCF, -H 470 «95 44 -OCH, 44 -OCH » • OCH, -H 460 «96 -H -H -OCH, -H • OCH » -H 430 «97 44 • 00.0 « 44 •H •H 428 1198 •H • OCH, •H -H 44 -OCH » 430 1199 •H -OCH, 44 -OCH, -H -OCH, 460 1200 •H • OCHF, 44 44 -H 44 436 1201 -H -H -Br • OCH, • OCH, -H 503 1202 -H 44 -CH, • OCH, -H -CH, 428 1203 • H 44 •H -OH 44 -H 366 1204 -H 44 -OCH, • OH -OCR, -H 446 1205 -H 44 -H • OH •H -OH 402 1206 -H Ή 44 44 -H -OCH, 400 1207 44 -F -H 44 -H 406 1208 -H 44 -H -3 · Ptridyl •H -H 447 1209 -H 44 •H -OCHjPh • Cl •H 510 1210 -H -H 44 -2-Thienyl •H -H 452 1211 44 -H -OCH, -OCH, • OCH, 44 460 1212 -H 44 -H •H ' -H 452 1213 -H 44 -H CH- »CHCH, O- -H -H 426 1214 44 -H 44 Phrolidinila -H -H 439 1215 -H aococHjO- -H •H -H -H 472 1218 -H 44 -H -OCH, Ι-Ο, Η, Ο- cycle -H 464 1217 -H •H CF, CFP- •H •H -H 504 1218 -H -H •H Mídazolila - -H -H 436 1219 •H -H 44 Píperedíno - -H 44 453 1220 -H •H -H 4-CF, Ph- 44 44 514 1221 44 44 44 4-CH, OPh- -H -H 476 1222 •H -H 44 {CH ^ NfCH ^ O- -H •H 471 1223 44 44 •H Morpholine * -AT THE, Ή 500 1224 44 Ή -H Piperedino- -N0, 44 498 1225 Ή -H -H 4-FPh · Ή 44 464 1226 -H •H -H 4-CH, (CH ₂ }, PI> -H -H 572 1227 Ή •H -H 3,4-FjPh- -H -H 4ΒΞ 1228 •H -H -H 4-CH ₃ (CKJ, Ph- -H -H 502 1229 •H •H -H 3-CM-FPh- -H -H 498

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Table 59

Example R1 R2 R3 FM R5 R5 MS 1230 • Η Ή • Η 4 * CF _# OPti · -H -H 530 1231 -Η Η -Η 4-CH.Fh- -H -H 450 1232 • Η -Η -Η 4-NCPh * -H H 471 1233 * Η -Η -Η 3.4- (0 ^ 0) ^ 1¼ -H -H 506 1234 -Η -ΟΟΗ, Ο- -H -H -H 414 1235 • Η -Η -OCMjO- -H -Cl 449 1236 • Η • OCHjO- *H -H 414 1237 Ή -Η * 0014.0 · -OCH) -H 444 1233 Ή -AT THE, . * Η -OCH _t O- -H 459 1239 Ή -Η • Η —N CH, -H 486

1240 Ή -Η

1241 · Η -Η

1242 -Η -Η

1243 -Η -Η

-Η -Ν02 617

-Η -ΝΟ2 589

-Η -OCH3 587

1244 -Η -Η -Η

1245

-Η

-Η

1246

Η • Η

-Η

-Η -Η 437

-Η -Η 625

-Η -Η 513

-Η · Η 4Θ6

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Table 60

Example R1

PffC) or -MS

1247

174.1-175.8

1248

1249

1250

218.8 - 220.1

201.9-203

156-158.3

1251

335

1252

Q

496

1253

513

1254

α

Q

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Table 61

12S7

CF,

182 · 185.7

125S

192J3 195.5

1259

216.4-215 ^

1260

1261

1262

196,197.8

212 ^ -212.9

219.2-220

1263

209.4-210.4

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HCCJou MS

205.4-206.6

420

1269

1270

463

450

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Table 63

37S

374

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Table 64

Example R1

PfÇC) or MS

360

374

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Table 66

Example Rj______________________PffC) or MS

1239

1290

1291

376

217.9-21 as

213.2-215.6

536

421

410

1296

404

524

524

466

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Table 67

1300

1301

376

421

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Table 70

Example

1325

1326

1327

PfÇÇ) or MS

607

461

499

1328

1329

453

437

377

1331

1B9.4-190.6

49B

1333

1334

1335

453

483

467

201.2-203.5

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Table 71

OMe ChLj

1340

469

1342

1343

467

543

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Table 73

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Table 74

Example R1 R2 R3 R4 R5 1PCQ '· 1362 -H •H • F -H •H 137-138 1363 -H •H -Cl -H •H 183 184 1364 •H -OCH * • OCH, • OCH, Ή 169 ^ 170 1365 -H -Cl -Ç) •H •H 174-175 1366 • Cl -H -H -H • Cl 208-209 1367 -F -F -H -H -H 184-185 1368 -H -F -F -H -H 185 -136 1369 -H -H -C0 ₂ CH, -H •H 183-184.5 1370 -CO ^ Hj -H -CO _to CJ4 ₍ •H 181 -182 1371 -H -H -OCH, -H -H 175-176 1372 -The -H -H -H •H 173-174.5 1373 -H -Cl -H -H •H 173-174 1374 Ή -CF, -H -H •H 184-186 1375 -CF * -H -H -H -H 188 - 190 1376 Ή -H -Fh -H Ή 187-108 1377 -H -CF, -H . -CF, •H 183 -184 1378 -F -F -F -F • F 235 - 237 1379 -H -H -SCH, -H -H 177-179 1380 -H -H • C (CH,),. -H -H 201 - 202 1381 -CH, -H -H -H -H 103-185 1382 • OCF, -H -H •H •H 190-191 1383 -H -OCF, -H -H •H 188-109

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Table 75

Example R4 1384 (CHJjÇH- 1385 (CHJ.CHCHj- 1386 1387 FhfCHJí- 1388 PhCH-CHCH _r 1389 FbfÇHJ, - 1890 (PhJiCH- 1391 Ph- 1392 2-NafptiU CH, - 1393 4-PyridylCHa- 1394 4-GFh (CHJ, · 1395 (4-CPh), CH · 1396. 4-Chy * h- 1397 4-CH »0Ph * 1393 2-BocNHPhCH, ·

1399 CHaOCHjCH, ·

251 * 253

233-235

219-220

199-200

180-131

188-137.5

202-204

242 * 244

173.5-174.5

183-164

198-200

208-240

230 * 231

243-250

144-145

1.8D-2J '(m, 2HJ, 2.1S-X25 (m, 2H). 3.30-3.40 (m, 5H), 3.68 (t, 2H, J - 4SH2); 8.85 * 4.20 [m. 4H> , 4.27 (t, 2H, J - 4.5Hz). 7.54 (s, 1H)

1.48 (s, 9H), 1.80-1 S5 (m, 2H). 2.05-2.15 (m, 2H), 2.40-2.50 (m. 4H), 2.66 (i, 2H, J => 5Hz} _f 3.25-3.45 (m, 6H), 3.90 * 4.10 (m. 4H). 4.24 (t _t 2H, J - 5Hz), 7.54 {s, JH)

1401

1SG-1S5 (m, 2H). 2/05 * 2.25 im _t 2H), 2.35-2.60 (m, 4H). 2.83-2.01 (m, 2H). 3.25-3.55 frn. '®HJ. 3.05-4.25 (m, 6H), 5.09 (s, 2H). 7Λ0-7.40 Jm.4H), 7.54 (s _t 1H)

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Table 76

R3

Sample 'F »R2 R3 R4

1402

1403

1404

140C

1406

1407

1403

4Í -H 44 -G

Ή • H

-H • Η -H

-H

Ή -H -F • H

-CF,

-OCF, -CH, Morpholine -CO, C (CHJ,

FS R6 Pfl * Ç) 249 -252 (4 «)

235 - 240 {diKj 215-217 23! -233> 300

240 - 245 (dec,)> 300 • H -M

-H

-H

-H

-H

1409

-H

205-207

1410 .1N —- CH,

44 -H

-H 240 - 250 (d «J

1411

-H 44 -F

-H -H 220 - 225 (deo)

Table 77

Ejetoratiplo R1

141Í PhCO

1413 HiCHjCO *

1414 Ph (CHj) _t CO *

1415 PhQCHiCO-

1410 CCH ^ CHCHiCO1417 4-CFjFhCO1410 PtiCHj-

~ PfÇCl ~ 170-100 170-171 160. s-es 203-205 214-215 165-166 249-251 (dec.) 262-264 (dec.)

1ô5-197 (deo.)

1421 ^ γΟ-ΟΟ 226-227 (dec.}

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Example 1422

Production of (S) -1 - (2-bromo-4-nitroimidazol-1-yl) -2-methyl-3- {4- [1 - (4trifluoromethoxyphenyl) pipendin-4-yl] piperazin-1-yl} propan-2-ol [3436] A mixture of (R) -2-bromo-4-nitro-1 - (2-methyl-2-oxiranylmethyl) imidazole (485 mg, 1.75 mmol), 1- [1- (4-trifluoromethoxyphenyl) pipendin-4-yl] piperazine (720 mg, 2.19 mmol) and ethanol (10 ml) was stirred at 50 ° C for 8 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 20/1) to obtain (S) -1- (2-bromo-4-nitroimidazole1 -il ) -2-methyl-3- {4- [1 - (4-trifluoromethoxyphenyl) pipendin-4-yl] piperazin-1-yl} propan-2-ol (792 mg, 77% yield) as a yellow amorphous form .

[3437] ¹ H NMR (CDCb) δ ppm:

[3438] 1.13 (3H, s), 1.50-1.75 (2H, m), 1.81-2.00 (21-1, m), 2.35 (1 H, d, J = 13.9 Hz),

2.40-2.86 (12H, m), 3.57-3.76 (2H, m), 3.98 (2H, s), 6.89 (2H, d, J = 8.5 Hz) , 7.09 (2H, d, J = 8.5 Hz), 8.12 (1 H, s).

[3439] The following compounds were produced in the same way.

Example 1423 ter-butyl (S) -4- {4- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazin-1yl} piperidine-1-carboxylate [ 3440] ¹ H NMR (CDCb) δ ppm:

[3441] 1.12 (3H, s), 1.29-1.48 (11H, m), 1.67-1.81 (2H, m), 2.34 (1H, d, J = 13, 8 Hz),

2.38-2.74 (12H, m), 3.97 (2H, s), 4.02-4.14 (2H, m), 8.05 (1 H, s).

Example 1424 ter-butyl (S) -4- {1 - [3- (2-chloro-4-nitroim idazol-1-yl) -2-hydroxy-2-methylpropyl] piperidin-4yl} piperazine-1-carboxylate [3442] ¹ H NMR (CDCb) δ ppm:

[3443] 1.11 (3H, s), 1.38-1.57 (11H, m), 1.69-1.86 (2H, m), 2.24-2.50 (9H, m) , 2,672.79 (1 H, m), 2.86-3.00 (1 H, m), 3.31 - 3.43 (4H, m), 3.95 (2H, s), 8.04 (1 H, s).

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Table 78

χ χχχ ^ Π N OH (K -. N II 0 XL

Example X R ¹ H NMR (CDCb) δ ppm 1425 none OCF3 1.13 (3H, s), 1.50-1.75 (2H, m), 1.81-2.00 (2H, m), 2.35 (1 H, d, J = 13.9Hz) , 2.40-2.86 (12H, m), 3,573.76 (2H, m), 3.98 (2H, s), 6.89 (2H, d, J = 8.5Hz), 7.09 (2H, d, J = 8.5 Hz), 8.12 (1 H, s). 1426 C = O Cl 1.13 (3H, s), 1.31-1.56 (2H, m), 1.70-2.00 (2H, m), 2.36 (1 H, d, J = 13.9Hz) , 2.65-2.91 (12H, m), 3,633.84 (1 H, m), 3.93 (2H, s), 4.56-4.74 (1 H, m), 7,197.42 (4H, m), 8.13 (1 H, s). 1427 c = o OCF3 1.14 (3H, s), 1.35-1.60 (2H, m), 1.74-2.00 (2H, m), 2.36 (1 H, d, J = 13.9Hz) , 2.42-2.93 (12H, m), 3,653.81 (1H, m), 4.00 (2H, s), 4.56-4.74 (1 H, m), 7.25 ( 2H, d, J = 8.7 Hz), 7.44 (2H, d, J = 8.7 Hz), 8.14 (1 H, s). 1428 ch ₂ Cl 1.12 (3H, s), 1.43-2.05 (6H, m), 2.34 (1 H, d, J = 13.9Hz), 2.37-2.95 (121-1, m), 3.47 (2H, s), 3.97 (21-1, s), 7.12-7.30 (4H, m), 8.12 (1 H, s). 1429 ch ₂ OCF3 1.12 (3H, s), 1.44-2.05 (6H, m), 2.35 (1 H, d, J = 14.0Hz), 2.42-2.93 (121-1, m), 3.48 (2H, s), 3.98 (21-1, s), 7.15 (2H, d, J = 8.6 Hz), 7.34 (2H, d, J = 8, 6 Hz), 8.12 (1 H, s).

Ο

Example X R ¹ H NMR (CDCb) δ ppm 1430 c = o Cl 1.12 (3H, s), 1.43-1.81 (4H, m), 2.10-2.62 (91-1, m), 2.71-3.07 (2H, m), 3.31 - 3.45 (41-1, m), 3.96 (21-1, s), 7.24-7.40 (41-1, m), 8.10 (1 H, s) . 1431 c = o OCF3 1.12 (3H, s), 1.45-1.83 (4H, m), 2.12-2.57 (91-1, m),

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2.71-3.07 (2H, m), 3.28-3.47 (4H, m), 3.96 (2H, s), 7.25 (2H, d, J = 8.6Hz), 7.45 (2H, d, J = 8.6 Hz), 8.10 (1 H, s). 1432 CH ₂ OCF3 1.11 (3H, s), 1.50-1.98 (4H, m), 2.24-3.10 (15H, m), 3.54 (2H, s), 3.98 (2H, s), 7.16 (2H, d, J = 8.6 Hz), 7.34 (2H, d, J = 8.6 Hz), 8.12 (1 H, s). 1433 ch ₂ Cl 1.11 (3H, s), 1.40-1.83 (4H, m), 2.25-3.02 (15H, m), 3.46 (2H, s), 3.95 (2H, s), 7.14-7.29 (4H, m), 8.12 (1 H, s). 1434 none OCF3 1.13 (3H, s), 1.50-1.64 (2H, m), 1.76-1.88 (2H, m), 2.15-2.43 (51-1, m), 2.52-2.95 (6H, m), 3.05-3.19 (41-1, m), 3.98 (21-1, s), 6.89 (2H, d, J = 8 , 7Hz), 7.11 (2H, d, J = 8.7Hz), 8.1 (1H, s). 1435 none Cl 1.13 (3H, s), 1.50-1.64 (2H, m), 1.71-1.90 (2H, m), 2.12-2.48 (51-1, m), 2.55-2.90 (6H, m), 3.05-3.19 (41-1, m), 3.96 (21-1, s), 6.84 (2H, d, J = 8 , 7Hz), 7.18 (2H, d, J = 8.7Hz), 8.11 (1H, s).

Table 80

Example X R ¹ H NMR (CDCb) δ ppm 1436 Cl 4-CIPh- 1.17 (3H, s), 2.41 (1H, d, J = 13.9Hz), 2.56 (11-1, d, J = 13.9Hz), 2.63-2.73 (2H , m), 2.76-2.92 (2H, m), 3.08-3.18 (4H, m), 3.40 (11-1, s), 4.01 (21-1, s ), 6.80-6.96 (61-1, m), 7.14-7.24 (21-1, m), 8.06 (1 H, s). 1437 Br 4-CF ₃ PhCH ₂ - 1.16 (3H, s), 2.39 (1 H, d, J = 13.9 Hz), 2.55 (1 H, d, J = 13.9 Hz), 2.65-2.78 (2H , m), 2.84-2.92 (2H, m), 3.02-3.14 (4H, m), 3.46 (1 H, s), 4.01 (2H, s), 5 , 08 (2H, s), 6.89 (4H, m), 7.48 (2H, d, J = 8.3Hz), 7.63 (2H, d, J = 8.3Hz), 8.12 (1 H, s). 1438 Br 4-CIPhCH ₂ - 1.16 (3H, s), 2.39 (1 H, d, J = 13.9 Hz), 2.55 (1 H, d, J = 13.9 Hz), 2.63-2.78 (2H , m), 2.80-2.96 (2H, m), 3.04-3.12 (4H, m), 3.47 (1 H, s), 4.01 (2H, s), 4 , 98 (2H, s), 6.88 (4H, s), 7.35 (4H, s), 8.12 (1 H, s).

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1439 Cl 4-CF ₃ OPhCH ₂ - 1.16 (3H, s), 2.40 (1 H, d, J = 13.9 Hz), 2.55 (1 H, d, J = 13.9 Hz), 2.65-2.76 (2H , m), 2.78-2.92 (2H, m), 3.04-3.12 (4H, m), 3.45 (1 H, s), 4.00 (2H, s), 5 , 0 (2H, s), 6.89 (4H, s), 7.22 (2H, d, J = 8.6Hz), 7.45 (2H, d, J = 8.6Hz), 8.06 (1H, s). 1440 Cl 4-CF ₃ OPh- 1.18 (3H, s), 2.41 (1H, d, J = 13.9Hz), 2.56 (11-1, d, J = 13.9Hz), 2.65-2.76 (2H , m), 2.78-2.88 (2H, m), 3.06-3.20 (4H, m), 3.39 (1 H, s), 4.02 (2H, s), 6 , 84-7.00 (6H, m), 7.14 (2H, d, J = 8.3 Hz), 8.06 (1 H, s). 1441 Cl 4-CF ₃ Ph- 1.18 (3H, s), 2.42 (1 H, d, J = 13.9 Hz), 2.57 (1 H, d, J = 13.9 Hz), 2.65-2.77 (2H , m), 2.79-2.92 (2H, m), 3.06-3.20 (4H, m), 3.40 (1 H, s), 4.03 (2H, s), 6 , 80-7.00 (6H, m), 7.53 (2H, d, J = 8.6 Hz), 8.07 (1 H, s).

Table 81

Example R ¹ H NMR (CDCb) δ ppm 1442 Cl- 1.17 (3H, s), 2.40 (1 H, d, J = 13.9 Hz), 2.55 (1 H, d, J = 13.9 Hz), 2.65-2.92 (4H, m), 3.08-3.24 (4H, m), 3.40 (2H, s), 4.00 (2H, s), 4.20 (2H, s), 6.54 (2H, d, J = 8.7Hz), 6.88 (2H, d, J = 8.7Hz), 7.09 (2H, d, J = 8.7Hz), 7, 18-7.25 (2H, m), 8.06 (1 H, s). 1443 cf ₃ o 1.16 (3H, s), 2.41 (1H, d, J = 13.9 Hz), 2.55 (1 H, d, J = 13.9 Hz), 2.65-2.92 (4H, m), 3.08-3.25 (4H, m), 3.44 (2H, s), 4.02 (2H, s), 4.21 (2H, s), 6.57 (2H, d, J = 8.6Hz), 6.89 (2H, d, J = 8.6Hz), 7.01 (2H, d, J = 8.3Hz), 7, 22 (2H, d, J = 8.3 Hz), 8.06 (1 H, s).

Table 82

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Example X R ¹ H NMR (CDCb) δ ppm 1444 Cl / ⁼ \ / 0 \ / ⁼ \ Vj / ^CF3 1.15 (3H, s), 1.51-1.86 (4H, m), 2,272.57 (3H, m), 2.75-2.92 (2H, m), 3,003.16 (2H, m), 3.56 (1 H, s), 4.17 (2H, s), 6.90-7.02 (4H, m), 7.10-7.25 (21-1, m), 7.56 (2H, d, J = 8.8 Hz), 8.01 (1H, s). 1445 Br 1.25 (3H, s), 1.50-2.00 (81-1, m), 2,242.67 (7H, m), 2.75-3.20 (4H, m), 3.97 ( 2H, s), 4.25-4.40 (1 H, m), 6.88 (2H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.8 Hz), 8 , 12 (1 H, s). 1446 Cl 0 4 /) OCF, H // 1.14 (3H, s), 1.76-1.93 (4H, m), 2,242.52 (5H, m), 2.74-2.86 (1 H, m), 2,953.07 (1 H, m), 3.98 (2H, s), 7.17 (2H, d, J = 8.8Hz), 7.55 (2H, d, J = 8.8Hz), 8.05 (1 H , s). 1447 Cl 0 ^An O ^^ ° ^cf3 1.13 (3H, s), 1.51-1.90 (4H, m), 2.192.55 (5H, m), 2.71-2.83 (1 H, m), 2,853.19 (51 -1, m), 3.51-3.83 (41-1, m), 3.98 (2H, s), 6.90 (2H, d, J = 8.3Hz), 7.13 (2H , d, J = 8.3 Hz), 8.05 (1 H, s). 1448 Cl the o 1.15 (3H, s), 1.39-1.83 (5H, m), 2,332.62 (3H, m), 3.00-3.15 (21-1, m), 3.493.61 ( 2H, m), 4.17 (2H, s), 6,977.05 (4H, m), 7.21-7.24 (21-1, m), 7,537.58 (2H, m), 8.08 (1 H, s) 1449 Cl - ° ^ sZj ^ ^ocFs 1.14 (3H, s), 1.61-1.81 (5H, m), 2,342.57 (3H, m), 2.77-2.84 (2H, m), 3.01 3.06 (2H, m), 3.99 (2H, s), 5.04 (2H, s), 6.89-6.95 (2H, m), 7.11-7.25 (4H, m), 7.43-7.48 (2H, m), 8.09 (1 H, s) 1450 Cl 1.14 (3H, s), 1.45-1.80 (5H, m), 2.382.60 (3H, m), 2.78-2.90 (2H, m), 3.01 3.06 (2H, m), 3.98 (2H, s), 5.11 (2H, s), 6.89-6.93 (2H, m), 7.12-7.18 (2H, m), 7.52-7.55 (2H, m), 7.62-7.65 (2H, m), 8.08 (1 H, s)

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1.14 (31-1, s), 1.38-1.80 (5H, m), 2.282.60 (3H, m), 2.77-2.93 (2H, m), 3.023.08 ( 2H, m), 3.98 (2H, s), 5.01 (2H, s), 6.84-6.92 (2H, m), 7.11-7.16 (2H, m), 7 , 32-7.36 (4H, m), 8.08 (1 H, s)

Table 83

Example R1 R2 ¹ H NMR (CDCb) δ ppm 1452 ⁰ I - / \ Ac ^ CH ₃ 1.13 (3H, s), 1.48 (9H, s), 2.42 (3H, s), 2.43 (2H, s), 3.03-3.13 (4H, m), 3 , 42 (1 H, d, J = 10.7 Hz), 3.50-3.63 (5H, m), 3.85 (2H, s), 6.84 (2H, d, J = 7.1 Hz ), 7.11 (2H, d, J = 7.1 Hz), 7.88 (1 H, s). 1453 ⁰ I C2H5 1.06-1.11 (61-1, m), 1.48 (91-1, s), 2.41 (1H, d, J = 13.2Hz), 2.55 (1 H, d, J = 13.2Hz), 2,642.68 (2H, m), 3.10-3.13 (4H, m), 3.42 (1H, d, J = 13.2Hz), 3.57-3 , 60 (4H, m), 3.69 (1 H, d, J = 13.2 Hz), 3.79 (2H, s), 6.83-6.86 (2H, m), 7.09- 7.12 (2H, m), 7.84 (1 H, s).

Example 1454

Production of (S) -2-methyl-6-nitro-2- {4- [1 - (4-trifluoromethoxyphenyl) pipendin-4-yl] piperazin1 -i Im ethyl} -2,3-di idroim idazo [2 , 1 -b] oxazole [3444] (S) -1 - (2-bromo-4-nitroimidazol-1-yl) -2-methyl-3- {4- [1 - (4trifluoromethoxyphenyl) pipendin-4-yl ] piperazin-1-yl} propan-2-ol (790 mg, 1.34 mmol) was dissolved in Ν, Ν-dimethylformamide (4 ml), sodium hydride (69 mg, 1.74 mmol) was added while it was cooled on ice, and the solution was stirred at the same temperature for 1 hour. Ethyl acetate (1.3 ml) and water (10 ml) in this order were added to the reaction mixture, and the precipitated crystals were removed by filtration and washed with water. The crystals were purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) and recrystallized from ethyl acetate / isopropyl ether to obtain (S) -2-methyl-6-nitro- 2- {4- [1- (4-trifluoromethoxyphenyl) iperidin-4

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818/854 yl] piperazin-1-ylmethyl} -2,3-dihydroimidazo [2,1-b] oxazole (270 mg, 40% yield) as a white powder.

[3445] Melting point 180-181.5 ° C.

[3446] The following compounds were produced in the same way.

Example 1455 (S) -2- {4- [4- (4-chlorophenyl) piperazin-1 -yl] piperidin-1-ylmethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [3447] 34% yield [3448] Melting point 226-228 ° C.

Example 1456 (S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenyl) piperazin-1-yl] pipendin-1-ylmethyl} -2,3dihydroimidazo [2,1-b] oxazole [3449] 23% yield [3450] Melting point 193-194 ° C.

Example 1457 (S) -2- {4- [4- (4-chlorobenzyl) piperazin-1 -yl] piperidin-1-ylmethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [3451] 25% yield [3452] Melting point 148-149 ° C.

Example 1458 (S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxybenzyl) piperazin-1-yl] pipendin-1-ylmethyl} 2,3-dihydroimidazo [2,1-b ] oxazole [3453] 21% yield [3454] Melting point 142-143 ° C.

Example 1459 (S) - (4-chlorophenyl) - {4- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperidin-4-yl] piperazin -1-yl} methanone [3455] 29% yield [3456] Melting point 174-175 ° C.

Example 1460

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819/854 (S) - {4- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] piperazin-1-yl} - (4-trifluoromethoxyphenyl) methanone [3457] 29% yield [3458] Melting point 137-138 ° C.

Example 1461 (S) -2- {4- [1- (4-chlorobenzyl) piperidin-4-yl] piperazin-1-ylmethyl} -2-methyl-6-nitro-2,3dihydroimidazo [2,1-b] oxazole [3459] 24% yield [3460] Melting point 168-169 ° C.

Example 1462 (S) -2-methyl-6-nitro-2- {4- [1- (4-trifluoromethoxybenzyl) pipendin-4-yl] piperazin-1-ylmethyl} 2,3-dihydroimidazo [2,1-b ] oxazole [3461] 27% yield [3462] Melting point 140-141 ° C.

Example 1463 (S) - (4-chlorophenyl) - {4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2i Im ethyl) piperazin-1 - il] piperid in-1 -yl} methanone [3463] 30% yield [3464] Melting point 218-220 ° C.

Example 1464 (S) - {4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin -1yl] piperidin-1-yl} - (4-trifluoromethoxyphenyl) methanone [3465] 27% yield [3466] Melting point 133-134 ° C.

Example 1465 (S) -1 '- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) -4- (4trifluoromethoxyphenoxy) - [1,4'] bipiperidinyl [3467] 41% yield [3468] Melting point 131-132 ° C.

Example 1466

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820/854

Production of (S) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] piperidine-1-carboxylate butyl [3469] A mixture of (R) -2-chloro-4-nitro-1- (2-methyl-2-oxiranylmethyl) imidazole (3 g, 13.79 mmol), 4-piperazin-1-yl-piperidine Tert-butyl -1-carboxylate (3.9 g, 14.48 mmol), and ethanol (30 ml) was stirred at 50 ° C for 9 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) to obtain a yellow amorphous form. The amorphous form was dissolved in N, N-dimethylformamide (18 ml), sodium hydride (651 mg, 16.28 mmol) was added while cooling on ice, and the resulting solution was stirred at the same temperature for 1 hour. Ethyl acetate (6 ml) and water (42 ml) in this order were added to the reaction mixture, and the precipitated crystals were removed by filtration and washed with water. The filtrate was recrystallized from 2-propanol (20 ml) / water (60 ml) to obtain (S) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b ] oxazol2-ylmethyl) piperazin-1-yl] piperidine-1-tert-butylcarboxylate (4.08 g, 66%) as a light yellow powder.

[3470] Melting point 181 -182 ° C.

[3471] The following compound was produced in the same way.

Example 1467 (S) -4- [1- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] piperazine-1-carboxylate ter- butyl [3472] 56% yield [3473] Melting point 184-185 ° C.

Example 1468

Production of 4- (S) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-methyl] piperazin-1-yl] piperidine-1-carboxylate trifluoromethoxybenzyl [3474] A mixture of 4- (trifluoromethoxy) benzyl alcohol (480 mg, 2.50 mmol), 1,1'-carbonylbis-1 H-imidazole (405 mg, 2.50 mmol), and N, N -dimethylformamide (3 ml) was stirred at room temperature for 14 hours.

[3475] Meanwhile, (S) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2ylmethyl) piperazin-1-yl] piperidine-1 - ter-butyl carboxylate (750 mg, 1.66 mmol) was

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821/854 dissolved in methylene chloride (5 ml), trifluoroacetic acid (5 ml) was added, and the resulting solution was stirred at room temperature for 14 hours. The reaction mixture was concentrated. Methanol (5 ml) and triethylamine (5 ml) were added to the residue, and the mixture was stirred at room temperature for 10 minutes and then concentrated. The residue was dissolved in Ν, Ν-dimethylformamide (5 ml). The solution was added to the Ν, Ν-dimethylformamide solution described above, followed by stirring at 50 ° C for 3 hours.

[3476] The reaction mixture was allowed to return to room temperature, poured into water (40 ml), and extracted with ethyl acetate (30 ml) twice. The organic phases were combined, washing with water (40 ml) twice, followed by a saturated saline solution (30 ml), and then drying over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) and then recrystallized from ethyl acetate / isopropyl ether to obtain (S ) 4-Trifluoromethoxybenzyl 4-[4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin-1-yl] piperidine-1-carboxylate (545 mg , 58%) as a light brown powder.

[3477] Melting point 105-106 ° C.

[3478] The following compound was produced in the same way.

Example 1469 (S) -4- [1 - (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperidin-4yl] piperazine-1-carboxylate 4 -trifluoromethoxybenzyl [3479] 64% yield [3480] Melting point 110-111 ° C.

Example 1470

Production of (S) -2-methyl-6-nitro-2- [4- {1 - [3- (4-trifluoromethoxyphenyl) -2-propenyl] pipendin4-yl} piperazin-1-ylmethyl] -2,3- dihydroimidazo [2,1-b] oxazol [3481] (S) -4- [4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazin1 - il] ter-butyl piperidine-1-carboxylate (750 mg, 1.66 mmol) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (5 ml) was added, followed by stirring at room temperature for 1 hour, 5 hours. The reaction mixture was concentrated.

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Methylene chloride (5 ml) and triethylamine (5 ml) were added to the residue, and the mixture was stirred at room temperature for 10 minutes and then concentrated. The residue was dissolved in 1,2-dichloroethane (20 ml), 3- (4trifluoromethoxyphenyl) propenal (396 mg, 1.83 mmol) and sodium triacetoxyborohydride (564 mg, 2.66 mmol) were added, followed by stirring. at room temperature for 3.5 hours. The reaction solution was washed with a saturated solution of sodium hydrogen carbonate (15 ml), water (20 ml), and a saturated saline solution (20 ml) in that order, and then dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (methylene chloride / methanol = 10/1) and then recrystallized from methanol / water to obtain (S) -2methyl- 6-nitro-2- [4- {1- [3- (4-trifluoromethoxyphenyl) -2-propenyl] piperidin-4-yl} piperazin-1ylmethyl] -2,3-dihydroimidazo [2,1-b] oxazole ( 446 mg, 49%) as a light yellow powder. [3482] Melting point 157-158 ° C.

[3483] The following compounds were produced in the same way. Example 1471 (S) -2-methyl-6-nitro-2- [4- {4- [3- (4-trifluoromethoxyphenyl) -2-propenyl] piperazin-1-yl} piperidin1 -i Im ethyl] -2 , 3-di idroim idazo [2,1-b] oxazole [3484] Melting point 174-175 ° C.

Example 1472 (S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) phenyl] piperazin-1-ylmethyl} -2,3dihydroimidazo [2,1-b] oxazole 4-toluenesulfonate [3485] Melting point 146.1 -148.6 ° C.

Example 1473 (S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) phenyl] piperazin-1-ylmethyl} -2,3dihydroimidazo [2,1-b] oxazole hydrochloride [3486 ] Melting point 133-137 ° C.

Table 84

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Example R1 R2 ¹ H NMR (CDCb) δ ppm 1474 0 CH, Λ J < ^CH3 CH ₃ 1.48 (9H, s), 1.55 (3H, s), 2.36 (3H, s), 2.61 (1H, d, J = 12.3Hz), 2.80 (11-1, d, J = 12.3Hz), 3.03-3.15 (4H, m), 3.41 (1H, d, J = 10.8Hz), 3.48-3.60 (5H, m), 3.69 (1H, d, J = 8.1Hz), 4.08 (1H, d, J = 8.1Hz), 6.85 (2H, d, J = 7.1Hz), 7.06 (2H , d, J = 7.1 Hz), 7.46 (1H, s). 1475 0 CH, AA ™ ³ C2H5 0.97 (3H, t, J = 7.1 Hz), 1.49 (9H, s), 1.53 (3H, s), 2.54-2.78 (3H, m), 2.93- 2.96 (1 H, m), 3.103.13 (4H, m), 3.39-3.43 (1 H, m), 3.57-3.67 (6H, m), 3.96 ( 1 H, d, J = 9.8 Hz), 6.83-6.85 (2H, m), 7.02-7.05 (2H, m), 7.43 (1 H, s). 1476 H CH3 1.53 (3H, s), 2.37 (3H, s), 2.60 (1 H, d, J = 12.2 Hz), 2.78 (1 H, d, J = 12.2 Hz), 2,983.18 (8H, m), 3.40 (1 H, d, J = 10.8 Hz), 3.55 (1 H, d, J = 10.8 Hz), 3.66 (1 H, d, J = 8.1 Hz), 4.04 (1 H, d, J = 8.1 Hz), 6.85 (2H, d, J = 7.1 Hz), 7.06 (2H, d, J = 7, 1 Hz), 7.45 (1 H, s). 1477 H C2H5 0.98 (3H, t, J = 7.1 Hz), 1.53 (3H, s), 2.552.75 (3H, m), 2.93-2.95 (1 H, m), 3.15 -3.18 (4H, m), 3.24-3.28 (4H, m), 3.37-3.43 (1 H, m), 3.62-3.67 (2H, m), 3.94 (1 H, d, J = 9.8 Hz), 6.82-6.87 (2H, m), 7.02-7.05 (2H, m), 7.44 (1 H, s ).

Table 85

Example R1 R2 mp (° C) 1478 -CH ₃ 4-CIPh- 202.6-204.0 dec 1479 -CH ₃ 4-CF ₃ PhCH ₂ - 172.0-174.2 1480 -CH ₃ 4-CIPhCH ₂ - 227.0-228.3 dec 1481 -CH ₃ 4-CF ₃ OPhCH ₂ - 176-179.5 1482 -CH ₃ 4-CF ₃ OPh- 114.1 -116.6 1483 -CH ₃ 4-CF ₃ Ph- 105-110

Table 86

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Example R1 R2 R3 mp (° C) 1484 -CH3 -CH3 1485 -CH ₃ -CH ₃ 1486 -CH ₃ -H 1487 -CH ₃ -H 4-CIPh- 4-CF ₃ OPh- 4-CIPh- 4-CF ₃ OPh- 126.2-127.5 103.0-106.6 209.8-210.3 dec 110.0-113.5

Table 87

Example R1 R2

mp (° C) or ¹ H NMR

1488

110.6-111.7

1489

1490

¹ H NMR (CDCb) δ ppm 1,561.71 (7H, m), 2.16 (3H, m), 2.57 (1 H, d, J = 14.9Hz), 2,763.10 (3H, m) , 3.93 (1 H, d,

J = 9.8 Hz), 4.36 (1 H, d, J = 9.8 Hz), 7.12 (2H, d, J = 8.5 Hz), 7,557.68 (3H, m), 9.04 (1 H, s).

¹ H NMR (CDCb) δ ppm 1.48-

1.68 (4H, m), 1.75-1.95 (1 H, m), 2.19-2.56 (4H, m), 2.75-3.19 (9H, m), 3 , 53-3.77 (4H, m), _F 3.88 (1 H, d, J = 9.7 Hz), 4.36 (1 H, d, J = 9.7 Hz), 6.89 (2H , d,

J = 8.5 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.68 (1 H, s).

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1491

1492

1493

1494

-CH ₃

-CH ₃

-CH ₃

-CH ₃

148.4-149.7

160.4-161.8

164.4-167.3 dec

140.2-142.8

Table 88

143.1 -145.8

1496

-CH ₃

Cl ¹ H NMR (CDCb) δΟ, 97 (3Η, t, J = 7.1 Hz), 1.51 (3H, s), 2,582.76 (7H, m), 2.89 (1 H, d, P _H J = 14.9Hz), 3.17-3.20 (41-1, m), ⁵ 3.38 (1 H, d, J = 13.3Hz), 3,543.64 (4H, m), 3 , 89 (1 H, d, J = 9.8 Hz), 6.82-6.85 (2H, m), 7.01-7.04 (2H, m), 7.27-7.30 (4H , m), 7.41 (1H, s).

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100.7-103.0 [3487] The following compounds were produced in the same manner as in Example 649.

Table 89

Example R Solvent ¹ H NMR δ ppm 1498 -Cl DMSO- in 1.32-1.50 (2H, m), 1.55-1.75 (2H, m), 2.863.02 (2H, m), 3.36-3.50 (2H, m), 4, 05 (2H, s), 4.93 (1 H, s), 6.95 (2H, d, J = 8.9Hz), 7.21 (2H, d, J = 8.9Hz), 8.35 (1 H, s). 1499 -OCF3 DMSO- in 1.51-1.67 (2H, m), 1.76-1.94 (2H, m), 2.02 (1H, s), 2.96-3.12 (2H, m), 3,373.56 (2H, m), 4.07 (2H, s), 6.9 (2H, d, J = 8.9Hz), 7.12 (2H, d, J = 8.9Hz), 8.00 (1H, s). 1500 ch ₃ CDCb 1.57-1.71 (2H, m), 1.78-1.98 (2H, m), 2,923.08 (2H, m), 3.24 (3H, s), 3.35- 3.51 (2H, m), 4.09 (2H, s), 6.74 (2H, d, J = 8.9Hz) , 6.88-7.10 (6H, m), 8.02 (1 H, s). 1501 ^{/ 0} ^ j ^ ^0CF 3 CDCb 1.55-1.69 (2H, m), 1.80-1.98 (2H, m), 2,923.08 (2H, m), 3.33-3.49 (2H, m), 4, 09 (2H, s), 6.82-6.98 (6H, m), 7.14 (2H, d, J = 8.9Hz), 8.02 (1H, s). 1502 - ⁿ ^ 2x ° ~ ^x '^^^ ^ocf3 CDCb 1.53-1.67 (2H, m), 1.80-2.16 (6H, m), 2,843.06 (4H, m), 3.24-3.45 (4H, m), 4.11 (2H, s), 4.33-4.47 (1 H, m), 6,806.92 (6H, m), 7.14 (2H, d, J = 8.9Hz), 8.00 (1 H, s).

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1.53-1.65 (2H, m), 1.82-1.98 (2H, m), 2.843.00 (2H, m), 3.14-3.39 (10H, m), 4, 07 (2H, s), 6.84-6.96 (6H, m), 7.14 (2H, d, J = 8.6 Hz), 8.01 (1 H, s).

[3488] The following compounds were produced in the same manner as in

Example 652.

Table 90

R1

Example

1504

1505

1506

1507

-Cl

mp (° C)

242.0 - 245.0

235.9-236.8dec.

214.0-215.1dec.

227.3-229.4

1508

1509

237.6-238.4

254.2 - 256.8 [3489]

The following compounds were produced in the same way as in the

Example 128.

Example 1510 (R) -2-methyl-6-nitro-2- {4- [1- (4-trifluoromethoxybenzyl) pipendin-4-yl] phenoxy methyl} -2,3 dihydroimidazo [2,1-b] oxazole [ 3490] Melting point 186-188 ° C.

Example 1511 (R) -6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) pipendin-1-yl] phenoxymethyl} -2,3

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828/854 dihydroimidazo [2,1-b] oxazole [3491] Melting point 157-160 ° C.

Example 1512

(R) -2-Methyl-6-nitro-2- {4- [3- (4-trifluoromethoxyphenoxy) -8azabicyclo [3,2,1] octan-8-yl] phenoxymethyl} -2,3-toluenesulfonate -dihydroimidazo [2,1-b] oxazole [3492] Melting point 207.2-208.0 ° C (decomposition).

Example 1513

2-methyl-6-nitro-2- [4- (4-trifluoromethoxyphenoxy) benzyloxymethyl] -2,3-dihydroimidazo [2,1b] oxazole [3493] Melting point 107.9-109.3 ° C.

Example 1514

6-Nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) piperidin-1-yl] phenoxymethyl} -2,3dihydroimidazo [2,1-b] oxazole [3494] Melting point 173,2-177,3 ° C.

Example 1515

2-methyl-6-nitro-2- {4- [4- (4-chlorophenoxy) piperidin-1-yl] phenoxymethyl} -2,3-dihydroimidazo [2,1b] oxazole [3495] Melting point 151.0 -152.3 ° C.

Example 1516 (S) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) piperidin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole [3496] Melting point 199.0-200.5 ° C.

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Example R1 R2 mp (° C) 1517 -CH ₃ -Cl 183.8-184 1518 -CH ₃ -CF ₃ 179.4- 180.9 1519 -CH ₃ -F 190.2 - 192.8 1520 -CH ₃ -OCH ₃ 193.3- 194.5 1521 -CH ₃ -CH ₃ 198.2-201.1 dec 1522 -CH ₃ -H 194.5 - 197.5 1523 -CH ₃ -CN 196.2-198.5 dec 1524 -H -OCF ₃ 157.0-160.0 1525 -H -Cl 166.5-171.0 dec

Table 92

Example R1 R2 R3 R4 R5 R6 MS (M + 1) 1526 -CH ₃ -och ₃ -H -H -H -H 481 1527 -CH ₃ -H -OCH ₃ -H -H -H 481 1528 -CH ₃ -H -H -OCH ₃ -H -H 481 1529 -CH ₃ -H -H -H -OCH ₃ -OCH ₃ 511 1530 -CH ₃ -OCH ₃ -H -H -H -och ₃ 511 1531 -CH ₃ -H -H -OCH ₃ -OCH ₃ -H 511 1532 -CH ₃ -H -OCH ₃ -H -och ₃ -H 511 1533 -CH ₃ -H -H -H -H -H 451 1534 -CH ₃ -H -H -H -H -Cl 485 1535 -CH ₃ -H -H -H -Cl -H 485 1536 -CH ₃ -H -H -Cl -H -H 485 1537 -CH ₃ -Cl -Cl -H -H -H 519 1538 -CH ₃ -Cl -H -Cl -H -H 519

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1539 -CH ₃ -Cl -H -H -Cl -H 519 1540 -CH ₃ -Cl -H -H -H -Cl 519 1541 -CH ₃ -H -Cl -Cl -H -H 519 1542 -CH ₃ -H -Cl -H -Cl -H 519 1543 -CH ₃ -H -H -H -H -CH ₃ 465 1544 -CH ₃ -H -H -H -CH ₃ -H 465 1545 -CH ₃ -H -H -CH ₃ -H -H 465 1546 -CH ₃ -CH ₃ -CH ₃ -H -H -H 479 1547 -CH ₃ -CH ₃ -H -CH ₃ -H -H 479 1548 -CH ₃ -CH ₃ -H -H -CH ₃ -H 479 1549 -CH ₃ -CH ₃ -H -H -H -CH ₃ 479 1550 -CH ₃ -H -CH ₃ -CH ₃ -H -H 479 1551 -CH ₃ -H -CH ₃ -H -CH ₃ -H 479 1552 -CH ₃ -H -H -H -H -F 469 1553 -CH ₃ -H -H -H -F -H 469 1554 -CH ₃ -H -H -F -H -H 469 1555 -CH ₃ -F -F -H -H -H 487 1556 -CH ₃ -F -H -F -H -H 487 1557 -CH ₃ -F -H -H -F -H 487 1558 -CH ₃ -F -H -H -H -F 487 1559 -CH ₃ -H -F -F -H -H 487 1560 -CH ₃ -CO2C2H5 -H -H -H -H 523 1561 -CH ₃ -H -CO2C2H5 -H -H -H 523 1562 -CH ₃ -H -H -CO2C2H5 -H -H 523 1563 -CH ₃ -CN -H -H -H -H 476 1564 -CH ₃ -H -CN -H -H -H 476 1565 -CH ₃ -H -H -CN -H -H 476 1566 -CH ₃ -H -H -H -H -CF ₃ 519 1567 -CH ₃ -H -H -H -CF ₃ -H 519

Example R1 R2 R3 R4 R5 R6 MS (M + 1) 1568 -CH ₃ -H -H -CF ₃ -H -H 519 1569 -CH ₃ -H -H -H -H -OCF ₃ 535 1570 -CH ₃ -H -F -H -F -H 487 1571 -CH ₃ -H -H -H -OCF ₃ -H 535 1572 -CH ₃ -H -H -OCF ₃ -H -H 535

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1573 -CH ₃ -H -H -H -H OCH (CH ₃ ) ₂ 509 1574 -CH ₃ -H -H -CH ₃ -H -CO2C2H5 537 1575 -CH ₃ -H -H -och ₃ -H -CO ₂ CH ₃ 539 1576 -CH ₃ -H -H -Br -H -F 547 1577 -CH ₃ -H -CH ₃ -H -H -F 483 1578 -CH ₃ -H -H -C3H7 -H -H 493 1579 -CH ₃ -H -H -Cl -F -H 503 1580 -CH ₃ -H -H -NO2 -H -F 514 1581 -CH ₃ -H -H -CH ₂ CH = CH2 -H -OCH ₃ 521 1582 -CH ₃ -H -H -H -CeHs -H 527 1583 -CH ₃ -H -H -H -N (C ₂ H ₅ ) 2 -H 522 1584 -CH ₃ -H -CH = CHCH ₃ (cis) -H -H -OC2H5 535 1585 -CH ₃ -H -H -CH (CH ₃ ) ₂ -H -H 493 1586 -CH ₃ -H -H -H NHCONH -H 509

1587 -CH ₃ -H -H CH2CH2COC H ₃ -H -H 521 1588 -CH ₃ -H -H -H -NHC6H5 -H 542 1589 -CH ₃ -H -H -NH2 -H -Cl 500 1590 -CH ₃ -H -H -CH ₂ CO2CH ₃ -H -H 523 1591 -CH ₃ -H -H -och ₃ -H -Cl 515 1592 -CH ₃ -H -H -H -CO ₂ CH ₃ -H 509 1593 -CH ₃ -H -H -COCH ₃ -H -CONH2 536 1594 -CH ₃ -H -H -COC2H5 -H -H 507 1595 -CH ₃ -H -H -COCH ₃ -H -CH ₃ 507 1596 -CH ₃ -H -H -coch ₃ -OH -H 509 1597 -CH ₃ -H -H -nhcoch ₃ -H -H 508 1598 -CH ₃ -H -CH ₃ -CH ₃ -CH ₃ -H 493 1599 -CH ₃ -H -H -H -H -CH2C6H5 541 1600 -CH ₃ -H -OCH ₃ -H -H -CO ₂ CH ₃ 539 1601 -CH ₃ -H -H -SCH ₃ -H -H 497 1602 -CH ₃ -H -H -CHF2 -H -H 517

Table 94

R1

0-R2 ° \

N // 0

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Petition 870190039560, of 26/04/2019, p. 843/876

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Table 98

Example R1 R2 R3 R4 mp (° C) or ¹ H NMR 1639 -CH ₃ -H -H -CH2C6H5 208-210.5 1640 -CH ₃ -H -H 4-BrPhCH ₂ - 213.5-215.4 1641 -CH ₃ -H -H 4-BrPhCH ₂ OCO- 185.4- 188.5 1642 -CH ₃ -H -H -Cycle-CeHu 255.4-257.9 dec 1643 -CH ₃ -H -H 4-CF ₃ PhCH = N- 178.0-278.6 1644 -CH ₃ -H -H 4-CF ₃ OPhOCO- 4- 226.5-226.8 1645 -CH ₃ -H -H CF ₃ PhCCCH ₂ OC 0- 186.4-187.7 1646 -H -H -H 4-CF ₃ OPh- 232.0-234.5 1647 -H -H -H 4-CF ₃ OPhCH ₂ - 171.4-172.9 1648 -H -H -H 4-CIPhCH ₂ - 191.2-192.0 ¹ H NMR (CDCb) δ 1.48 (9H, s), 2.993.04 (4H, m), 3.55-3.60 (4H, m), 4.22- 1649 -H -H -H (CH ₃ ) ₃ COCO- 4.37 (2H, m), 4.39-4.49 (2H, m), 5,565.63 (1 H, m), 6.79-6.91 (41-1, m), 7.63 (1 H, s).

Table 99

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Example R1 R2 R3 R4 R5 MS (M + 1) 1650 -H -cf ₃ -H -H -H 518 1651 -H -H -NO2 -H -H 495 1652 -H -H -CF ₃ -H -H 518 1653 -H -H -CH ₃ -H -H 464 1654 -H -H -CN -H -H 475 1655 -H -H -CeHs -H -H 526 1656 -H -H -F -H -H 468 1657 -H -Cl -Cl -H -H 518 1658 -cf ₃ -H -H -H -H 518 1659 -H -H -OCH ₃ -H -H 480 1660 -H -H -sch ₃ -H -H 496 1661 -H -H -so ₂ ch ₃ -H -H 528 1662 -H -H -OCH2C6H5 -H -H 556 1663 -H -Cl -H -Cl -H 518 1664 -F -F -F -H -H 504 1665 -H -H -OCOCH ₃ -H -H 508

Table 100

Example R1 MS (M + 1) 1666 4-CF ₃ OPh- 564 1667 4-CH ₃ OPhCH ₂ - 524 1668 4-CH ₃ PhCH ₂ - 508 1669 4-CH ₃ O ₂ CPhCH2- 552 1670 -CH2C6H5 494 1671 4-CH ₃ SPhCH ₂ - 540 1672 4-NO ₂ PhCH2- 539 1673 3,4,5- (CH ₃ O) ₃ PhCH ₂ - 584 1674 2-CH ₃ CONHPhCH ₂ - 551 1675 4-FPhCH ₂ - 512 1676 4-CF ₃ OPhCH ₂ - 578 1677 4-PhCH ₂ OPhCH2- 600 1678 4-CF ₃ SPhCH ₂ - 594 1679 3-CF ₃ OPhCH ₂ - 578 1680 2-CF ₃ OPhCH ₂ - 578 1681 C6F5CH2- 584 1682 PhCH = CHCH ₂ - 520 1683 4-CIPhCH = CHCH ₂ - 554 1684 4-CF ₃ OPhCH = CHCH ₂ - 604 1685 - (CH2) 2CeH5 508

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1686 Ph (CH ₂ ) ₃ - 522 1687 PhCCCH ₂ - 518 1688 PhS (CH ₂ ) ₂ - 540 1689 PhCH ₂ O (CH ₂ ) ₂ - 538 1690 -CH ₂ CH ₂ CH = CH ₂ 458 1691 -ch ₂ ch ₂ cn 457 1692 CH ₃ (CH ₂ ) 15- 628 1693 CH ₃ CH ₂ O (CH ₂ ) ₂ O (CH ₂ ) ₂ - 520 1694 -ch ₂ ch ₂ cch 456 1695 cf ₃ cf ₂ cf ₂ ch ₂ - 586 1696 -CH ₂ -cycle-C ₃ H5 458

Table 101

1699

484

1700

584

1701

596

1702

1703

634

495

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Table 102

Example R1 MS (M + 1) 1707 520 1708 ¹ ò 529 1709 ^ oo 544

Table 103

Example R1 MS (M + 1) 1710 -CH ₂ CH = CH2 400 1711 -CeHi3 444 1712 -CH ₂ CN 399 1713 - (CH ₂ ) ₂ CH (CH ₃ ) ₂ 430 1714 -CH ₂ CON (CH ₃ ) ₂ 445

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Example R1 R2 mp (° C) or ¹ H NMR 1715 -CH ₃ 4-CF ₃ OPh- 157.9-158.8 1716 -CH ₃ 4-CF ₃ OPhCH ₂ - 188.4-190.2 1717 -CH ₃ 4-CF ₃ OPhCH ₂ OCO- 112.1 -115.4 1718 -CH ₃ 4-CF ₃ OPhCO- 1719 -CH ₃ 4-CF ₃ OPhNHCO-

Table 105

R1

Example R1 R2 R3 mp (° C) 1720 -H 4-CF ₃ OPh- -CH ₃ 126.9-128.9 1721 -H 4-CF ₃ OPh- -C ₂ Hs 102.1 - 103.1 1722 -H 4-CIPh- -C ₂ Hs 121.7 -123.6 1723 -H -CeHs -CH ₃ 169.5-171.0 1724 -H 4-CF ₃ OPhCH ₂ - -CH ₃ 134.8- 136.8 1725 -H 4-CIPhCH ₂ - -CH ₃ 161.4-164.1 1726 -H 4-CF ₃ PhCH ₂ - -CH ₃ 136.4- 137.9 1727 -H 4-CF ₃ OPhCH ₂ - -C ₂ Hs 119-120.5 1728 -H 4-CF ₃ PhCH ₂ - -C ₂ Hs 134.3- 135.7 1729 -H 4-CIPhCH ₂ - -C ₂ Hs 135.8-137 1730 -F 4-CF ₃ OPhCH ₂ - -CH ₃ 132.7-134.7 1731 -H 4-CF ₃ OPhCH ₂ - 4-CF ₃ OPhCH ₂ - 135.9-137 1732 -H 4-CF ₃ OPhCH ₂ - -CeHs 198.9-200.8 1733 -H 4-CF ₃ PhCH ₂ - -CeHs 192.7-194.7 1734 -H 4-CIPhCH ₂ - -CeHs 195.1 - 196.1 1735 -H -CeHs -COCH ₃ 167.7-168.7 1736 -H 4-CIPh- -coch ₃ 220.0-223.5 1737 -H 4-CF ₃ Ph- -coch ₃ 223.1 -224.6 1738 -H 4-CF ₃ OPh- -coch ₃ 243.6-244.9 1739 -F 4-CIPh- -coch ₃ 221.8-223.0

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1740 -F 4-CF ₃ OPh- -COCH ₃ 240.3-242.9 1741 -Η -CeHs -co ₂ ch ₃ 182.7-184.8 1742 -Η 4-CIPh- -co ₂ ch ₃ 244.0-245.1 1743 -Η 4-CF ₃ OPhCH ₂ - -H 151.4-154.3 1744 -Η 4-CF ₃ OPhCH ₂ - -CO ₂ C ₂ H5 105.1 - 107.6 1745 -Η 4-CIPh (CH ₂ ) ₂ - -CH ₃ 116.1 -117.6 1746 -Η 4-CF ₃ OPhO (CH ₂ ) ₃ - -H 189.9-191.0 1747 -Η 4-CF ₃ OPhCO- -CH ₃ 143.3-145.9

R1

Example R1 R2 R3 ¹ H NMR 1748 -H ¹ H NMR (CDCb) δ 1.80 (3H, s), 3.28 (3H, s), 4.06 (1 H, d, J = 10.2 Hz), 4.11 (1 H, d, J = 10.2Hz), 4.26 (4-CF ₃ Ph- CH ₃ 1H, d, J = 10.2Hz), 4.52 (1 H, d, J = 10.2Hz), 6.70 (2H, d, J = 8.7Hz), 6.88 (2H, d, J = 8.8Hz), 7.13 (2H, d, J = 8.8Hz), 7.39 (2H, d, J = 8.7 Hz), 7.57 (1 H, s). 1749 -H ¹ H NMR (CDCb) δ 1.79 (3H, s), 3.22 (3H, s), 4.04 (1 H, d, J = 10.4Hz), 4.08 (1 H, d, 4 p.ph _ΓΗ J = 10.4Hz), 4.23 (11-1, d, J = 10.1Hz), 4.50 (11-1, d, J = 10.1Hz), 6.70- 6.73 (2H, m), 6.81-6.84 (21-1, m), 7.03-7.06 (2H, m), 7.12-7.15 (2H, m), 7.56 (1 H, s). 1750 -H ¹ H NMR (CDCb) δ 1.20 (31-1, d, J = 7.1 Hz), 1.81 (3H, s), 3.71 (2H, q, J = 7.1 Hz), 4, 07 (11-1, d, J = 10.2Hz), 4.11 (11-1, d, 4-CF ₃ Ph- -C ₂ H ₅ J = 10.2Hz), 4.27 (1 H, d, J = 10.2Hz), 4.52 (1 H, d, J = 10.2Hz), 6.63-6.66 (2H, m), 6.88-6.91 (21-1, m), 7.10-7.12 (2H, m), 7.34-7.37 (2H, m), 7.57 (1 H, s). 1751 -F ¹ H NMR (CDCb) δ 1.80 (31-1, s), 3.20 (3H, 4-CIPh-CH ₃ s), 4.06 (1 H, d, J = 10.2 Hz), 4.09 (1 H, d, J = 10.1 Hz), 4.25 (11-1, d, J = 10.1 Hz),

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4.49 (1 H, d, J = 10.2 Hz), 6.54-6.57 (2H, m), 6.64-6.71 (2H, m), 7.09-7.19 (31-1, m), 7.57 (1 H, s). 1752 -H 4-CF ₃ OPhCH ₂ -COCH ₃ ¹ H NMR (CDCb) δ 1.79 (3H, s), 1.85 (3H, s), 4.06 (1 H, d, J = 10.2 Hz), 4.08 (1 H, d, J = 10.2Hz), 4.24 (1 H, d, J = 10.2Hz), 4.48 (1 H, d, J = 10.2Hz), 4.82 (2H, s), 6.786, 82 (2H, m), 6.88-6.91 (2H, m), 7,097.11 (2H, m), 7.20-7.22 (2H, m), 7.56 (1 H, s ). 1753 -H 4-CF ₃ OPhCO- -CH ₃ ¹ H NMR (CDCb) δ 1.76 (3H, s), 3.45 (3H, s), 4.03 (1 H, d, J = 10.1 Hz), 4.04 (1 H, d, J = 10.2Hz), 4.18 (1H, d, J = 10.1Hz), 4.46 (1 H, d, J = 10.2Hz), 6.69-6.72 (2H, m) , 6.95-6.98 (2H, m), 7.37-7.46 (4H, m), 7.55 (1 H, s). 1754 -H 4-CIPhCO- -CH ₃ ¹ H NMR (CDCb) δ 1.77 (3H, s), 3.43 (3H, s), 4.03 (1 H, d, J = 10.1 Hz), 4.04 (1 H, d, J = 10.2Hz), 4.18 (1H, d, J = 10.1Hz), 4.46 (1 H, d, J = 10.2Hz), 6.69-6.72 (2H, m) , 6.94-6.97 (2H, m), 7.13-7.23 (4H, m), 7.55 (1 H, s). 1755 -H 4-CIPhCO- -H ¹ H NMR (DMSO) δ 1.68 (3H, s), 4.174.20 (1 H, m), 4.22-4.30 (2H, m), 4,364.39 (1 H, m), 6 , 88-6.91 (2H, m), 7,577.66 (4H, m), 7.94-7.97 (2H, m), 8.15 (1 H, s), 10.19 (1 H , brs).

Example R1 R2

1756 -H 4-CIPhCOR3 ¹ Η NMR ¹ Η NMR (DMSO) δ 1.68 (3H, s), 4.174.20 (1 Η, m), 4.22-4.30 (2Η, m), 4, 36-Η 4.39 (1 Η, m), 6.88-6.91 (2Η, m), 7,577.66 (4Η, m), 7.94-7.97 (2Η, m),

8.15 (1 Η, s), 10.19 (1 Η, brs).

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1757

-H 4-CF ₃ PhCO1758

-Η 4-CF ₃ OPhCO-

1759

1760

1761

1762

1763

1764

-Η 4-CIPh-Η 4-CF ₃ OPh (CH ₂ ) ₂ -Η 4-CF ₃ OPh (CH ₂ ) ₂ -Η 4-CF ₃ OPhO (CH ₂ ) ₃ -Η 4-CF ₃ OPhCOCH ₂ - Η 4-CF ₃ OPhCOCH ₂ ¹ Η NMR (DMSO) δ 1.68 (3Η, s), 4,174.21 (1 Η, m), 4.24-4.30 (2Η, m), 4.36 _Η 4.40 (1 Η, m), 6.90-6.93 (2Η, m), 7,657.68 (2Η, m), 7.88-7.90 (2Η, m), 8,118.13 (21 -1, m), 8.16 (1Η, s), 10.35 (1Η, brs).

¹ Η NMR (DMSO) δ 1.68 (3Η, s), 4.174.20 (1 Η, m), 4.24-4.31 (2Η, m), 4.36 _Η 4.40 (1 Η, m), 6.89-6.92 (2Η, m), 7,497.52 (2Η, m), 7.63-7.66 (2Η, m), 8,048.06 (2Η, m), 8.16 (1 Η, s), 10.23 (1 Η, brs).

-Η 142.6-144.7

-Η

-CH ₃

-C ₂ H ₅ 107.6- 109.2

-Η

-CH ₃

Table 108

R1

R2

I

N

R3

Example R1 R2 R3

1765 -CH ₃ -h 4-CIPh- 1766 -ch ₃ -h 4-CF ₃ Ph- 1767 -CH ₃ -CH ₃ 4- CF ₃ OPhCH ₂ - 1768 -ch ₃ -h 4-CF ₃ OPh- 1769 -CH ₃ -coch ₃ 4-CF ₃ OPh- 1770 -CH ₃ -CH ₃ 4-CF ₃ OPh- 1771 -CH ₃ -CH ₃ 4-CF ₃ Ph- 1772 -CH ₃ -coch ₃ 4-CF ₃ Ph- 1773 -CH ₃ -CH ₃ 4-CIPh-

1774 -CH ₃ -CO ₂ C ₂ H ₅ 4-CF ₃ OPhp.f. (° C) or ¹ H NMR__________________

171.5-173.5

172.2-174.9

138.5-141.0

165.1 -167.2

128.4-130.8

113.6-114.5

168.2 -170.7

132.8-133.9

160.9-163.4 ¹ H NMR (CDCb) δ 1.21 (3H, t, d = 7.1), 1.77 (31-1, s), 4.05 (1 H, d, J = 10 , 3Hz), 4.06 (1H, d, J = 10.2Hz), 4.15-4.22 (3H, m), 4.49 (1H, d, J = 10.3Hz), 4 , 78 (2H, s), 6.74-6.78 (2H, m), 7.07-7.13 (6H, m), 7.55 (1 H, s).

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844/854 ¹ H NMR (CDCb) δ 1.78 (3H, s), 1.86 (3H, s), 4.03 (1 H, d, J = 10.2Hz), 4.05 (1 H , d, J = 10.1Hz), 4.21 (11-1, d, J = 10.1Hz), 1775 -CH3 -COCH ₃ 4-CIPh- 4.48 (1 H, d, J = 10, 2Hz), 4.78 (2H, s),

6.71-6.74 (21-1, m), 6.87-6.89 (2H, m), 7.08-7.11 (2H, m), 7.28-7.32 (2H , m), 7.55 (1 H, s).

Table 109

Example R1 R2 mp (° C) 1776 -CH ₃ -4-PYRIDILLA 228.2-229.8 dec 1777 -CH ₃ -CHO 176.0- 179.5 1778 -CH ₃ 4-CIPhCO- 186.2 - 188.5 1779 -CH ₃ 4-CF ₃ PhCO- 170.3- 172.4 1780 -CH ₃ 4-CF ₃ OPhCO- 159.7 - 160.7 Table 110

Example R1 R2

mp (° C) or ¹ H NMR

1781

177.4-184.3

1782

1783

-CH ₃

-CH ₃

196.3-197.8

212.3-214.0

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1784

1785

1786

1787

1788

1789

1790

-CH ₃

251.9-253.0

216.7-219.5 dec

248.1 -248.2

150.3-154.9

150.8-151.2 ¹ H NMR (CDCb) δ 1.55 (1 H, s), 1.60 (1H, s), 1.77 (3H, s), 1.80-1.95 ( 2H, m), 2.15-2.40 (21-1, m), 3.043.27 (2H, m), 3,

33-3.53 (21-1, m), 3.95-4.11 (2H,

m), 4.19 (1H, d, J = 10.2Hz), 4.50 (1 H, d, J = 10.2

Hz), 6.71-6.86 (2H, m), 6.887.02 (2H, m), 7.14-7.31 (2H, m), 7.47-7.63 (3H, m) .

¹ H NMR (DMSO) δ 1.67 (3H, s), 2.61 (2H, brs), 3.74 (2H, d, J = 2.9Hz), .17 (1 H, d, J = 13.0Hz), 4.21 (2H, s), 6.28 (1 H, s), 6.81 (2H, d, J = 9.1Hz), 6.94 (2H, d, J = 9 , 2Hz), 7.18-7.57 (5H, m), 8.17 (1H, s).

Table 111

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Example R1 R2

mp (° C) or ¹ H NMR

1791

1792

1793

1794

-CH ₃

1795

1796

-CH ₃

-CH ₃

202.0-203.5

206.0

247.8-249.8

-CH ₃

ÇH ₃

97.7-99.7

-CH ₃

-CH ₃

172.5-175.8

160.7-163.0

1797

¹ H NMR (CDCb) δ 1.81 (3H, s), 3.44 (3H, s), 4.06 (1 H, d, J = 10.24Hz), 4.12 (1 H, d, J = 10.0 Hz), 4.27 (1 H, d, J = 10.0 Hz), 4.52 (1 H, d, J = 10.2 Hz), 6.83-6.91 (2H, m ), 7.39-7.45 (2H, m), 7.51-7.56 (31-1, m), 7.57 (1 H, s), 7.62-7.68 (2H, m)

Example R1

R2

Table 112

mp (° C) or ¹ H NMR

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1798

1799

1800

¹ H NMR (CDCb) δ 1.80 (31-1, s), 4,014.14 (2H, m), 4.26 (1 H, d, J = 10.0 Hz), 4.51 (11-1 , d, J = 10.3Hz), 6.85 (2H, d, J = 8.6Hz), 7.03-7.09 (4H, m), 7.537.60 (4H, m), 7.66 (1 H, s) ¹ H NMR (CDCb) δ 1.81 (31-1, s), 4.05 (11-1, d, J = 10.3Hz), 4.11 (11-1, d , J = 10.0 Hz), 4.26 (1 H, d, J = 10.0 Hz), 4.51 (1H, d, J = 10.3 Hz), 6.83-7.05 (4H, m ), 7.20-7.26 (2H, m), 7.51-7.60 (41-1, m), 7.65 (1 H, s)

1801

1802

1803

Table 113

Example R1 R2 R3 R4 R5 MS (M + 1) 1804 -Η -cf ₃ -Η -Η -Η 517

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1805 -H -H -NO2 -H -H 494 1806 -H -H -CF ₃ -H -H 517 1807 -H -H -CH ₃ -H -H 463 1808 -H -H -CN -H -H 474 1809 -H -H -CeHs -H -H 525 1810 -H -H -F -H -H 467 1811 -H -Cl -Cl -H -H 517 1812 -cf ₃ -H -H -H -H 517 1813 -H -H -OCH ₃ -H -H 479 1814 -H -H -sch ₃ -H -H 495 1815 -H -H -so ₂ ch ₃ -H -H 527 1816 -H -H -OCH ₂ CeHs -H -H 555 1817 -H -Cl -H -Cl -H 517 1818 -F -F -F -H -H 503 1819 -H -H -OCOCH ₃ -H -H 507

Table 114

Example R1 MS (M + 1) 1820 4-CF ₃ OPh- 563 1821 4-CH ₃ OPhCH ₂ - 523 1822 4-CH ₃ PhCH ₂ - 507 1823 4-CH ₃ O ₂ CPhCH ₂ - 551 1824 -CH ₂ CeHs 493 1825 4-CH ₃ SPhCH ₂ - 539 1826 4-NO ₂ PhCH ₂ - 538 1827 3,4,5- (CH ₃ O) ₃ PhCH ₂ - 583 1828 2-CH ₃ CONHPhCH ₂ - 550 1829 4-FPhCH ₂ - 511 1830 4-CF ₃ OPhCH ₂ - 577 1831 4-PhCH ₂ OPhCH ₂ - 599 1832 4-CF ₃ SPhCH ₂ - 593 1833 3-CF ₃ OPhCH ₂ - 577 1834 2-CF ₃ OPhCH ₂ - 577 1835 CeFsCH ₂ - 583 1836 PhCH = CHCH ₂ - 519 1837 4-CIPhCH = CHCH ₂ - 553 1838 4-CF ₃ OPhCH = CHCH ₂ - 603 1839 - (CH ₂ ) ₂ CeH5 507 1840 Ph (CH ₂ ) ₃ - 521

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1841 PhCCCH ₂ - 517 1842 PhS (CH ₂ ) 2- 539 1843 PhCH ₂ O (CH ₂ ) ₂ - 537 1844 -CH ₂ CH ₂ CH = CH ₂ 457 1845 -CH2CH2CN 456 1846 CH3CH ₂ O (CH2) 2O (CH ₂ ) 2- 519 1847 -CH2CH2CCH 455 1848 CF3CF2CF2CH2- 585 1849 -CH2-CYCI0-C3H5 457

Table 115

Example R1 MS (M + 1)

1850

494

494

1852

483

1853

1854

583

595

1855

499

1856

494

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Table 117

Example R1 MS (M + 1) 1863 -CH ₂ CH = CH2 399 1864 - (CH ₂ ) ₂ C6H5 463 1865 -CeHi3 443 1866 -CH ₂ CN 398 1867 -CH ₂ CON (CH ₃ ) ₂ 444

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Example R1 R2 mp (° C) 1869 -CH ₃ 4-CF ₃ PhCH ₂ - 171.4-172.4 1870 -CH ₃ 4-CF ₃ PhCH ₂ OCO- 130.4-131.7 1871 -CH ₃ 4-CIPhCH ₂ OCO- 126.8-129.1 1872 -CH ₃ 4- CF ₃ OPhCH ₂ OCO- 143.8-144.8 1873 -CH ₃ 4-CIPhCH ₂ - 183.0-187.2 1874 -CH ₃ 4-CF ₃ OPhCH ₂ - 174.3-176.5 1875 -CH ₃ 4-CF ₃ Ph- 156.7 -157.7 1876 -CH ₃ (CH ₃ ) ₃ COCO- 197.0-198.2 1877 -CH ₃ 4-CF ₃ OPh- 154.5-156.7

Table 119

Example R1 R2 mp (° C) or ¹ H NMR 1878 -CH ₃ 4-CIPhCH ₂ - 214.3-216.1 1879 -CH ₃ 4-CF ₃ Ph- 158.5-160.1 1880 -CH ₃ 4-CF ₃ OPh- 161.7-164.4 1881 -CH ₃ 4-CIPh- 163.5-166.3 ¹ H NMR (CDCb) δ 1.76 (3H, s), 4.02 (1 H, d, J = 10.2Hz), 4.04 (11-1, d, J = 10.2Hz), 4.18 (1 H, d, 1882 -CH ₃ 4-CF ₃ OPhCH ₂ - J = 10.2Hz), 4.48 (1 H, d, J = 10.2Hz), 5.00 (2H, s), 6.77-6.81 (2H, m), 6.85-6 , 90 (2H, m), 7.21-7.23 (2H, m), 7.42-7.45 (2H, m), 7.54 (1 H, s). ¹ H NMR (CDCb) δ 1.77 (3H, s), 4.02 (1 H, d, 1883 -CH ₃ 4-CF ₃ PhCH ₂ - J = 10.2Hz), 4.04 (11-1, d, J = 10.2Hz), 4.18 (1 H, d, J = 10.2Hz), 4.49 (1 H, d, J = 10.2Hz), 5.07 (2H, s), 6.77-6.81 (2H, m), 6.85-6 , 91 (2H, m), 7.51-7.55 (3H,

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m), 7.62-7.65 (21-1, m).

Example 1884

Production of (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) pipendin-1 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1 -b] oxazole [3497 ] 4- [4- (4-trifluoromethoxyphenoxy) pipendin-1-yl] phenol (693 mg, 1.96 mmol) was dissolved in Ν, Ν'-dimethylformamide (3 ml), added and sodium hydride (86 mg, 2.16 mmol) while cooling on ice, followed by stirring at 70-75 ° C for 20 minutes. The mixture was cooled on ice. A solution prepared by dissolving (R) -2-bromo-4-nitro-1- (2-methyl-2-oxiranylmethyl) imidazole (720 mg, 2.75 mmol) in Ν, Ν'- dimethylformamide (3 ml), followed by stirring at 70-75 ° C for 20 minutes. The reaction mixture was allowed to return to room temperature, water with ice (25 ml) was added, and the resulting solution was extracted with methylene chloride (50 ml) three times. The organic phases were combined, washing with water 3 times, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (methylene chloride / ethyl acetate = 3/1). Recrystallization from ethyl acetate / isopropyl ether gave (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethoxyphenoxy) pipendin-1yl] phenoxymethyl} -2,3-dihydroimidazo [2, 1-b] oxazole (343 mg, 33%) as a light yellow powder.

Example 1885

Production of 3- (4-trifluoromethylphenyl) -2-propenyl (S) -4- [3- (2-bromo-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl] piperazine-2-propenyl [3498 ] A mixture of 3- (4) (R) -2-bromo-4-nitro-1- (2-methyl-2-oxiranylmethyl) imidazole (2.04 g, 7.78 mmol), piperazine-1-carboxylate -trifluoromethylphenyl) -2-propenyl (2.69 g, 8.56 mmol) and Ν, Ν'-dimethylformamide (10 ml) was stirred at 50 ° C for 20 hours. The reaction solution was allowed to return to room temperature, water was added, and the resulting solution was extracted with ethyl acetate (15 ml) twice. The organic phases were combined, washed with water three times, and dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was

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853/854 purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/2) to obtain (S) -4- [3- (2-bromo-4-nitroimidazole-1- yl) 3- (4-trifluoromethylphenyl) -2-propenyl -2-hydroxy-2methylpropyl] piperazine-1-carboxylate (3.77 g, 84%) as a yellow oil.

[3499] ¹ H NMR (CDCl3) δ ppm:

[3500] 1.16 (3H, s), 2.36 (1H, d, J = 14.0 Hz), 2.43 - 2.76 (5H, m), 3.21 (1H, s),

3.41 - 3.57 (4H, m), 4.01 (2H, s), 4.78 (2H, dd, J = 1.0 Hz, 6.1 Hz), 6.29 - 6.43 (1H, m), 6.66 (1H, d, J = 16 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.58 (2H, d, J = 8, 3 Hz), 8.10 (1H, s).

Production of 3- (4-trifluoromethylphenyl) -2-propenyl (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-2-propenyl [3501] (S) -4- [3- (2-bromo-4-nitroimidazol-1-yl) -2-hydroxy-2-methyl Ipropyl] 3- (4-trifluoromethylphenyl) piperazine-1 carboxylate - 2-propenyl (3.5 g, 6.07 mmol) was dissolved in Ν, Ν'-dimethylformamide (10.5 ml), and sodium hydride (316 mg, 7.89 mmol) was added while cooling over ice, followed by stirring at the same temperature for 1.5 hours. To the reaction solution, ethyl acetate (3.5 ml) and water (24.5 ml) were added, followed by stirring for 30 minutes. The precipitated crystals were removed by filtration, washed with water, and purified by column chromatography on silica gel (ethyl acetate). Recrystallization from 2-propanol / water gives a light yellow powder of (S) -4- (2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-ylmethyl) piperazine-1carboxylate 3- (4-trifluoromethylphenyl) -2-propenyl (2.07 g, 69%).

Test Example 1 [3502] Antimicrobial assay (agar dilution method) [3503] The minimum inhibitory concentration of the compound 2,3-dihydro-6nitroimidazo [2,1-b] oxazole obtained in Example 397 against Micobacterium tuberculosis (M. tuberculosis H37Rv) was determined using a 7H11 medium (manufactured by BBL). The above strain had been grown in a 7H9 medium (manufactured by BBL) in advance, the number of viable cells was counted, and a cell suspension was prepared with the final viable cell count of approximately 10 ⁶ CFU / ml using if a cell suspension stored at -80 ° C. 5 μΙ of

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854/854 cell suspension thus prepared was inoculated on 7H11 agar medium containing the test compound and then cultured at 37 ° C for 14 days. Then, the culture was subjected to the test to determine the minimum inhibitory concentration.

[3504] The minimum inhibitory concentration of the compound against M. tuberculosis H37Rv was 0.024 pg / ml.

Claims (8)

1. Compound, characterized by the fact that 2,3-dihydro-6-nitroimidazo [2,1b] oxazole is represented by the following general formula (1), optically active form, or pharmaceutically acceptable salt thereof: R ¹ O ₂ N (CH ₂ ) _n R ² where R ¹ represents a hydrogen atom or C 1 -C 6 alkyl group, n represents an integer from 0 to 6, and R ² represents a group represented by the general formula (E) indicated below: a phenoxy group represented by the following general formula (E): (X) m R where X represents a halogen atom or C1-6 alkyl group substituted by amino which may have a C1-6 alkyl group as a substituent, m represents an integer from 0 to 3, and R ¹¹ represents: E1) hydrogen atom; E10) piperidyl group represented by the following general formula (Eaa): -(Won R ¹⁴ r ^14A (Eaa) where W represents a -CO- group or a C1-6 alkylene group, o represents an integer 0 or 1, R ^14A represents a hydrogen atom, hydroxyl group, C1-6 alkoxy group, or phenyl group (which can be replaced by halogen in the phenyl ring); the dashed line represents that the bond can be a double bond, and when the dashed line represents a double bond, this means that only R ¹⁴ is substituted; R ¹⁴ and R ^14A can bond together with carbon atoms adjacent to it to form a C 1-4 alkylenedioxy group, and R ¹⁴ represents: (Eaa1) hydrogen atom; Petition 870190084003, of 08/28/2019, p. 8/15 2/7 (Eaa2) Ci-e alkoxycarbonyl group; (Eaa3) phenoxy group (which can be substituted on the phenyl ring by a group selected from the group consisting of a halogen atom; an unsubstituted or substituted C1-6 alkyl group; an unsubstituted or substituted C1-6 alkoxy group by halogen; a C1-4 alkylenedioxy group; a C1e alkoxycarbonyl group; a cyano group; a C2-6 alkenyl group; a nitro group; a phenyl group; an amino group that may have, as a substituent, a group selected from the group consisting of a phenyl group, a C1-6 alkyl group, a carbamoyl group and a C1-6 alkanoyl group; a C1-6 alkyl group substituted by C1-6 alkanoyl; a hydroxyl group; a C1-6 alkyl group substituted by C1-6 alkoxycarbonyl; a phenyl C1-6 alkyl group; a C1-6 alkanoyl group; a C1-6 alkylthio group; a 1,2,4-triazolyl group; an isoxazolyl group; an imidazolyl group; a benzothiazolyl group; a benzothiazolyl group; 2H-benzotriazolyl group; a pyrrolyl group; a benzoxazolyl group; a gas piperazinyl group (which can be substituted on the piperazine ring by a group selected from the group consisting of a C1-6 alkoxycarbonyl group and a phenyl C1-6 alkyl group (which can be substituted on the phenyl ring by a group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent); a piperidinyl group (which can be substituted on the piperidine ring by a group selected from the group consisting of an amino group (which can be substituted on the amino group by a group selected from the group consisting of a C1-6 alkyl group and a phenyl group (which can be substituted on the phenyl ring by a group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen) as a substituent), and a carbamoyl group)); (Eaa4) hydroxyl group; (Eaa5) carboxy group; (Eaa6) phenyl group (which can be substituted on the phenyl ring by a group selected from the group consisting of a phenoxy group (which can be substituted on the Petition 870190084003, of 08/28/2019, p. 9/15 3/7 phenyl ring by a group selected from the group consisting of a halogen atom, a C1-6 alkyl group unsubstituted or substituted by halogen, and a C1-6 alkoxy group unsubstituted or substituted by halogen as a substituent), a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted or substituted C1-6 alkoxy group as a substituent); (Eaa7) C1-6 alkoxy group; (Eaa8) C3-8 cycloalkyl group - C1-8 alkoxy; (Eaa9) phenylcarbamoyl group (which can be substituted on the phenyl ring by a group selected from the group consisting of a halogen atom, an unsubstituted or substituted C1-6 alkyl group, and an unsubstituted C1-6 alkoxy group or replaced by halogen); (Eaa10) tetrahydropyranyloxy group; (Eaa11) 1,3-dioxolanyl group; (Eaa12) oxo group; (Eaa13) naphthyloxy group (which can be substituted on the naphthalene ring by a C1-6 alkyl group as a substituent); (Eaa14) 2,3-dihydrobenzofuryloxy group (which can be substituted on the 2,3-dihydrobenzofuran ring by a group selected from the group consisting of a C1-6 alkyl group and an oxo group); (Eaa15) benzothiazolyloxy group (which can be substituted on the benzothiazole ring by a C1-8 alkyl group); (Eaa16) 1,2,3,4-tetrahydronaphthoxy group (which can be substituted on the 1,2,3,4-tetrahydronaphthalene ring by an oxo group as a substituent); (Eaa17) 1,3-benzoxathiolaniloxy group (which can be substituted on the 1,3benzoxathiolane ring by an oxo group as a substituent); (Eaa18) isoquinolyloxy group; (Eaa19) pyridyloxy group; (Eaa20) quinolyloxy group (which can be substituted on the quinoline ring by a C1-6 alkyl group as a substituent); Petition 870190084003, of 08/28/2019, p. 10/15 4/7 (Eaa21) dibenzofuryloxy group; (Eaa22) 2H-chromenyloxy group (which can be substituted on the 2Hchromene ring by an oxo group as a substituent); (Eaa23) benzisoxazolyloxy group; (Eaa24) quinoxalyloxy group; (Eaa25) 2,3-dihydro-1 H-indenyloxy group (which can be substituted on the ring 2.3-dihydro-1 H-indene by an oxo group as a substituent); (Eaa26) benzofurazaniloxy group; or (Eaa27) C2-6 phenyl alkenyl group (which may be substituted on the phenyl ring by a group selected from a group consisting of a halogen atom, an unsubstituted or substituted halogen C1-6 alkyl group, and an alkoxy group C16 not replaced or replaced with halogen). 2. 2,3-Dihydro-6-nitroimidazo [2,1-b] oxazole compound according to claim 1, characterized in that it is selected from the following list of compounds: 2-methyl-6-nitro-2- {4- [4- (4-thfluoromethoxyphenoxy) pipehdin-1-yl] phenoxymethyl} - 2.3- dihydroimidazo [2,1-b] oxazole, (S) -2-methyl-6-nitro-2- {4- [4- (4-thfluoromethoxyphenoxy) pipehdin-1il] phenoxymethyl} -2,3-dihydroimidazo [ 2,1-b] oxazole, (R) -2-methyl-6-nitro-2- {4- [4- (4-thfluoromethoxyphenoxy) piperidin-1 yl] phenoxymethyl} -2,3-dihydroimidazo [2,1 -b] oxazole, 6-nitro-2- {4- [4- (4-thfluoromethoxyphenoxy) pipehdin-1-yl] phenoxymethyl} -2,3dihydroimidazo [2,1 -b] oxazole, (S) -6-nitro-2- {4 - [4- (4-thfluoromethoxyphenoxy) pipehdin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole, (R) -6-nitro-2- {4- [4- (4-thfluoromethoxyphenoxy ) pipehdin-1-yl] phenoxymethyl} -2,3 dihydroimidazo [2,1-b] oxazole, 2-methyl-6-nitro-2- {4- [4- (4-chlorophenoxy) pipehdin-1-yl] phenoxymethyl} -2,3dihydroimidazo [2,1-b] oxazole, (S) -2-methyl- 6-nitro-2- {4- [4- (4-chlorophenoxy) pipehdin-1-yl] phenoxymethyl} -2,3 Petition 870190084003, of 08/28/2019, p. 11/15 5/7 dihydroimidazo [2,1-b] oxazole, (R) -2-methyl-6-nitro-2- {4- [4- (4-chlorophenoxy) piperidin-1-yl] phenoxymethyl} -2, 3diidroimidazo [2,1-b] oxazole, 2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylphenoxy) -piperidin-1-yl] phenoxymethyl} -2,3dihydroimidazo [2,1-b] oxazole, (S) -2-methyl -6-nitro-2- {4- [4- (4-trifluoromethylphenoxy) piperidin-1-yl] phenoxymethyl} - 2.3- dihydroimidazo [2,1-b] oxazole, (R) -2-methyl-6-nitro-2- {4- [4- (4-trifluoromethylphenoxy) piperidin-1-yl] phenoxymethyl} - 2.3- dihydroimidazo [2,1-b] oxazole. A 2,3-dihydro-6-nitroimidazo [2,1-b] oxazole compound according to claim 1, characterized in that it is (R) -2-methyl-6-nitro-2- {4- [ 4- (4trifluoromethoxyphenoxy) pipendin-1-yl] phenoxymethyl} -2,3-dihydroimidazo [2,1-b] oxazole. 4. Pharmaceutical composition, characterized by the fact that it is an antituberculous agent comprising, as an active ingredient, the compound 2,3-dihydro-6nitroimidazo [2,1-b] oxazole, optically active form thereof, or its pharmacologically acceptable salt as defined in claim 1. Pharmaceutical composition according to claim 4, characterized in that it comprises, as an active ingredient, a compound selected from the 2,3-dihydro-6-nitroimidazo [2,1-b] oxazole compounds as defined in the claim 2. 6. Pharmaceutical composition according to claim 4, characterized in that it comprises, as an active ingredient, the compound as defined in claim 3. 7. Method for producing a compound represented by the following general formula (1a): Petition 870190084003, of 08/28/2019, p. 12/15 6/7 where R ¹ , R ^{2 and} n are defined as in claim 1, characterized by the fact that it comprises: a reaction of a compound 4-nitroimidazole represented by the following general formula (2): H where Xi represents a halogen atom or nitro group, with an epoxy compound represented by the following general formula (3a): (3a) wherein R ¹ , R ^{2 and} n are defined as in claim 1, in order to obtain a compound represented by the following general formula (4a): (4a) wherein R ¹ , R ^{2 and} n are defined as in claim 1, and Xi represents a halogen atom or nitro group; and the following ring closure of the compound obtained represented by the general formula (4a) above. 8. Method for producing a compound represented by the general formula (1 b) below: (1b) the ₂ n where R ¹ is as defined in claim 1, and R ^2a represents a group Petition 870190084003, of 08/28/2019, p. 13/15 7/7 represented by the general formula (E) as defined in claim 1, characterized by the fact that it comprises: the reaction of a compound represented by the following general formula (3b): R ¹ (3b) 10 ₂ N ^/ ^^ N where R ¹ is as defined in claim 1, and Xi represents a halogen atom or nitro group, with a compound (5) represented by the general formula R ^2a H (5) below or a salt thereof, wherein R ^2a represents the group represented by the general formula (E) as defined in claim 1, in order to obtain a compound represented by the following general formula (4b): (4b) wherein R ¹ is as defined in claim 1, R ^2a represents the group represented by the general formula (E) as defined in claim 1, and Xi represents a halogen atom or nitro group; and the following ring closure of the compound obtained represented by the general formula (4b) above.